Szczepionka bcg przeciwko gruźlicy – Patofizjologia i mechanizm

Szczepionka bcg przeciwko gruźlicy
Patofizjologia i mechanizm

Szczepionka BCG, będąca żywą atenuowaną szczepionką z osłabionego Mycobacterium bovis, pozostaje jedyną zatwierdzoną szczepionką przeciwko gruźlicy. Jej skuteczność jest zmienna i wynosi średnio około 50% w zapobieganiu gruźlicy płuc u dorosłych, natomiast w profilaktyce ciężkich postaci gruźlicy u dzieci (zapalenie opon mózgowo-rdzeniowych i postać prosówkowa) sięga 70-80%. Metaanalizy wskazują na redukcję ryzyka infekcji o 19-27% oraz progresji do aktywnej choroby o 71%. Mechanizm działania BCG opiera się na indukcji odpowiedzi immunologicznej Th1 z dominującą rolą limfocytów T CD4+ wydzielających IFN-γ, aktywujących makrofagi, a także na aktywacji limfocytów T CD8+ oraz innych populacji komórek T (γδ, MAIT, CD1-zależnych). Szczepionka wywołuje również wyszkoloną odporność (trained immunity) poprzez epigenetyczne przeprogramowanie monocytów i makrofagów, co wzmacnia niespecyficzną odpowiedź immunologiczną i zapewnia ochronę przed różnorodnymi patogenami, w tym wirusami układu oddechowego.

Mechanizm działania szczepionki BCG przeciwko gruźlicy

Szczepionka BCG (Bacillus Calmette-Guérin) to jedyna aktualnie dostępna i zatwierdzona szczepionka przeciwko gruźlicy. Jest to żywa atenuowana szczepionka uzyskana z osłabionego szczepu Mycobacterium bovis, blisko spokrewnionego z Mycobacterium tuberculosis – bakterią wywołującą gruźlicę u ludzi.¹² Została opracowana przez Alberta Calmette’a i Camille’a Guérina, którzy po 230 pasażach i 13 latach badań uzyskali osłabiony szczep, który był bezpieczny i zapewniał ochronę przed M. tuberculosis.³⁴ Szczepionka BCG została po raz pierwszy podana człowiekowi w 1921 roku i od tego czasu jest najszerzej stosowaną szczepionką na świecie.¹⁵

Skuteczność szczepionki BCG

Efektywność szczepionki BCG różni się znacząco w zależności od populacji i regionu geograficznego, wykazując ochronę w zakresie od 0 do 80%. Średnia skuteczność w zapobieganiu gruźlicy płuc u dorosłych wynosi około 50%.⁶⁷ Metaanaliza przeprowadzona w 2014 roku wykazała, że szczepionka BCG zmniejsza ryzyko infekcji o 19-27% oraz redukuje progresję do aktywnej gruźlicy o 71%.⁶

Szczepionka BCG wykazuje najwyższą skuteczność w zapobieganiu ciężkim postaciom gruźlicy u dzieci, zapewniając 70-80% ochrony przed zapaleniem opon mózgowo-rdzeniowych na tle gruźliczym i postacią prosówkową gruźlicy.⁸⁷⁹ Przegląd systematyczny wykazał, że BCG zapewnia również ochronę przed samym zakażeniem M. tuberculosis, a nie tylko przed progresją z zakażenia utajonego do aktywnej choroby.¹⁰ Szacowany ogólny współczynnik ryzyka wynosi 0,81, co wskazuje na 19% skuteczność ochronną przed infekcją u dzieci zaszczepionych w porównaniu z niezaszczepionymi.¹¹

Patogeneza i odpowiedź immunologiczna po szczepieniu BCG

Zrozumienie mechanizmu działania szczepionki BCG wymaga analizy złożonych interakcji immunologicznych, które zachodzą po jej podaniu. Szczepionka wywołuje szereg reakcji immunologicznych, które przygotowują organizm do obrony przed M. tuberculosis.¹²

Indukcja odpowiedzi immunologicznej

Po podaniu szczepionki BCG, zazwyczaj drogą śródskórną, następuje lokalna infekcja i aktywacja układu immunologicznego. Komórki układu odpornościowego, takie jak monocyty, makrofagi i komórki dendrytyczne, wchodzą w interakcję z bakteriami BCG.¹³ BCG internalizowane przez komórki dendrytyczne może przeżyć do 2 tygodni wewnątrz tych komórek, wywołując zwiększoną ekspresję cząsteczek kostymulujących i produkcję cytokin polaryzujących odpowiedź immunologiczną.¹⁴

Aktywowane komórki dendrytyczne migrują do okolicznych węzłów chłonnych, gdzie następnie wydzielają TNF-α, IL-6 i IL-12, aktywując zarówno limfocyty T CD4+, jak i CD8+.¹⁴ Szczepionka BCG indukuje odpowiedzi immunologiczne skierowane przeciwko szerokiemu spektrum antygenów mykobakteryjnych, co stanowi jej zaletę w porównaniu do szczepionek podjednostkowych.¹²

Rola limfocytów T w ochronie po szczepieniu BCG

Odpowiedź immunologiczna wywołana przez BCG jest zdominowana przez limfocyty T CD4+ o profilu Th1, które wydzielają interferon gamma (IFN-γ). IFN-γ odgrywa kluczową rolę w ochronie przed gruźlicą, aktywując makrofagi do zwalczania infekcji mykobakteryjnej.¹⁴ Udowodniono to w badaniach, gdzie osoby z mutacjami genów kodujących IFN-γ wykazywały zwiększoną podatność na zakażenie gruźlicą.¹⁴

Oprócz limfocytów T CD4+, coraz więcej dowodów wskazuje na istotną rolę limfocytów T CD8+ w ochronnej odpowiedzi immunologicznej przeciwko M. tuberculosis. Niewystarczająca aktywacja limfocytów T CD8+ może być jednym z powodów ograniczonej skuteczności BCG w zapewnianiu długotrwałej ochrony przed gruźlicą.¹⁵

W odpowiedzi na szczepionkę BCG zaangażowane są również inne typy komórek T, w tym limfocyty T γδ, limfocyty T związane z błoną śluzową (MAIT) oraz limfocyty T CD1-zależne, które przyczyniają się do odporności indukowanej przez BCG.¹⁶

Wyszkolona odporność (trained immunity)

Wyszkolona odporność (trained immunity) to stosunkowo nowo odkryty mechanizm działania szczepionki BCG, polegający na epigenetycznym przeprogramowaniu komórek odporności wrodzonej, które zapewnia niespecyficzną ochronę przed różnymi patogenami.¹⁷¹⁸

Mechanizm ten opiera się na reprogramowaniu epigenetycznym monocytów/makrofagów i komórek NK, które nabywają pamięć niespecyficzną i reagują szybciej oraz silniej na wtórne zakażenia różnymi mikroorganizmami.¹⁸ Szczepionka BCG indukuje modyfikacje histonów i przeprogramowanie epigenetyczne w ludzkich monocytach w miejscach promotorowych genów kodujących cytokiny prozapalne, takie jak TNF-α i IL-6.¹⁹

Udowodniono, że zmiana metylacji histonów H3K4me3 zależna od receptora NOD2 jest mechanizmem, dzięki któremu BCG wzmacnia wrodzone odpowiedzi immunologiczne.¹⁷ Przeprogramowanie epigenetyczne jest regulowane przez zmiany w metabolizmie komórek odpornościowych, co dodatkowo wzmacnia efekt ochronny.¹⁷

Niespecyficzna ochrona przed innymi patogenami

Jednym z najbardziej interesujących aspektów działania szczepionki BCG jest jej zdolność do zapewniania niespecyficznej ochrony przed innymi patogenami niż M. tuberculosis.¹³ Badania kliniczne sugerują, że BCG może być skuteczna przeciwko infekcjom wywoływanym przez patogeny wirusowe, takie jak wirus syncytialny układu oddechowego, wirus brodawczaka ludzkiego i wirus opryszczki pospolitej.¹³

Mechanizmy, dzięki którym BCG zapewnia niespecyficzną ochronę przed infekcjami układu oddechowego, opierają się na dwóch głównych procesach:¹⁸

Heterologiczna odporność limfocytów T, która zapewnia krzyżową ochronę poprzez heterologiczne odpowiedzi pamięci limfocytów T
Wyszkolona odporność (trained immunity), polegająca na przeprogramowaniu komórek odporności wrodzonej, które zapewniają niespecyficzną pamięć odpowiedzi immunologicznej

¹⁸

Niedawne badanie ujawniło nowy mechanizm krzyżowej ochrony zapewnianej przez BCG przeciwko wirusowi grypy typu A. Odkryto, że redukcja obciążenia wirusowego była zależna od interakcji między limfocytami T pamięci a makrofagami pęcherzykowymi w płucach.²⁰ Jest to wcześniej nieznany mechanizm krzyżowej ochrony, podkreślający komunikację między adaptacyjnym i wrodzonym układem immunologicznym.²⁰

Ograniczenia i wyzwania związane z mechanizmem działania BCG

Mimo szerokiego stosowania szczepionki BCG, jej skuteczność jest zmienna, co wynika z kilku czynników związanych z mechanizmem jej działania.²¹

Delecja systemu sekrecji ESX-1

Jednym z głównych ograniczeń szczepionki BCG jest brak systemu sekrecji ESX-1, który został utracony w wyniku delecji fragmentu chromosomu podczas atenuacji.²² System ESX-1 w M. tuberculosis umożliwia bakterii naruszenie integralności błony fagosomu makrofaga, w którym jest zamknięta. Pęknięcie tej błony powoduje kontakt składników mykobakteryjnych z cytosolem komórki gospodarza, co jest sygnałem do wywołania kaskady odpowiedzi immunologicznej wrodzonej przyczyniającej się do kontroli wzrostu mykobakterii.²²

Konwencjonalny BCG pozostaje uwięziony w fagosomie i nie komunikuje się w znaczącym stopniu z cytosolem komórki gospodarza, co ogranicza jego zdolność do wywoływania pełnej odpowiedzi immunologicznej.²³ Naukowcy z Instytutu Pasteura opracowali szczep rekombinowany BCG wykazujący system sekrecji ESX-1 z Mycobacterium marinum, który wywołuje wzmocnione odpowiedzi immunologiczne i wykazuje lepszą ochronę przed infekcją M. tuberculosis niż konwencjonalna szczepionka BCG.²³

Ekspozycja na niegruźlicze mykobakterie (NTM)

Najważniejszym czynnikiem wpływającym na skuteczność BCG, popartym danymi, jest ekspozycja na niegruźlicze mykobakterie (NTM) występujące powszechnie w środowisku.²⁴ Istnieją dwie hipotezy dotyczące mechanizmu, poprzez który ekspozycja na NTM zmniejsza skuteczność BCG:²⁴

Mechanizm „maskowania” – wcześniejsza ekspozycja na NTM wywołuje odpowiedź immunologiczną, która chroni przed BCG
Mechanizm „blokowania” – wcześniejsza ekspozycja na NTM blokuje replikację BCG, co ogranicza jej immunogenność

²⁴

Badania wykazały, że chroniczna ekspozycja doustna na mykobakterie środowiskowe prowadzi do ogólnoustrojowej tolerancji przeciwko mykobakteriom. Ta tolerancja generuje słabą odpowiedź immunologiczną w scenariuszu następującego później śródskórnego szczepienia BCG, co może prowadzić do zmiennej skuteczności szczepionki.²⁵

Droga podania szczepionki

Standardowa droga podania szczepionki BCG to droga śródskórna, co może być jednym z powodów jej nieskuteczności w wywoływaniu długotrwałej pamięci immunologicznej w płucach i niejednolitego poziomu ochrony przed gruźlicą płuc u dorosłych.²⁶ W ostatnich latach wzrosło zainteresowanie alternatywnymi drogami podania, takimi jak droga śluzówkowa i dożylna, które wykazały lepszą odpowiedź immunologiczną zarówno w układzie ogólnoustrojowym, jak i śluzówkowym.²⁶

Badania na makakach wykazały, że dożylne podanie BCG zapewnia znacznie lepszą ochronę przed gruźlicą, wywołując silniejszą odpowiedź limfocytów T CD4+ w płucach i może zapewnić jeszcze bardziej skuteczną ochronę niż standardowe BCG.²⁷ Zaobserwowano sterylizującą odporność u 6 z 8 makaków w porównaniu z 2 z 8 makaków immunizowanych standardowym BCG.²⁷

Ponadto, badania na myszach narażonych na mykobakterie środowiskowe wykazały, że immunizacja płucna BCG generuje odporność niezależnie od wcześniejszej ekspozycji na mykobakterie środowiskowe, ponieważ tolerancja ogólnoustrojowa nie występuje w drogach oddechowych gospodarza.²⁵

Nowe kierunki w badaniach nad szczepionkami BCG

Z uwagi na ograniczoną skuteczność BCG, szczególnie przeciwko gruźlicy płuc u dorosłych, prowadzone są intensywne badania nad ulepszeniem tej szczepionki lub opracowaniem nowych szczepionek przeciwgruźliczych.²⁸

Rekombinowane szczepy BCG

Bezpieczeństwo i znajomość kliniczna BCG skłoniły do rozwoju rekombinowanych szczepów BCG (rBCG) w celu poprawy odpowiedzi immunologicznych wywoływanych przez szczepienie.²⁸ Manipulacja genetyczna ułatwia konstrukcję rekombinowanej szczepionki BCG, która może być stosowana jako wysoce immunogenna szczepionka przeciwko gruźlicy z ulepszonym profilem bezpieczeństwa.²⁹

Rekombinowany szczep BCG ekspresjonujący ESX-1 (BCG::ESX-1) wykazuje większą ochronę niż BCG typu dzikiego w modelach mysich i świnkach morskich, chociaż ten rekombinowany szczep jest bardziej zjadliwy.²⁴ Innym przykładem jest BCG zmp1, który wykazuje zwiększone dojrzewanie fagosomu i fuzję fagolizosomów, wspomagając prezentację antygenu, co prowadzi do poprawy ochrony.²⁴

Niedawno opracowano samodestrukcyjną, dożylną szczepionkę BCG z wbudowanym mechanizmem bezpieczeństwa – „wyłącznikiem” BCG – który eliminuje możliwość przypadkowej samoinfekcji osłabionymi mykobakteriami, oferując bezpieczny i skuteczny sposób zwalczania gruźlicy.³⁰

Szczepionki wielostadiowe

Patogeneza M. tuberculosis postępuje kolejno przez pierwotną infekcję, latencję i reaktywację. Podczas tych stadiów infekcji metabolizm i profile transkrypcji genów M. tuberculosis wykazują znaczące różnice i cechy specyficzne dla danego stadium in vivo.³¹ Dlatego opracowywane są szczepionki wielostadiowe, które zawierają antygeny wyrażane podczas różnych stadiów infekcji M. tuberculosis.

Przykładem takiej szczepionki jest H56, która zawiera Ag85B i ESAT-6, dwa antygeny M. tuberculosis wydzielane w ostrej fazie infekcji, oraz antygen Rv2660c indukowany stresem odżywczym.³² Badania na makaków wykazały, że wzmocnienie BCG szczepionką H56 opóźnia i zmniejsza chorobę kliniczną u makaków zakażonych M. tuberculosis oraz zapobiega reaktywacji latentnej infekcji.³²

Innym przykładem jest podjednostkowa szczepionka A1D4, składająca się z czterech antygenów związanych z fazą latencji i jednego antygenu wydzielanego związanego z fazą pierwotnej infekcji. Badania na myszach wykazały, że szczepionka ta zapewnia skuteczną ochronę przed infekcją M. tuberculosis.³³

Podsumowanie mechanizmu działania BCG

Szczepionka BCG przeciwko gruźlicy działa poprzez złożone mechanizmy immunologiczne, które obejmują zarówno odporność wrodzoną, jak i adaptacyjną. Główne elementy jej działania to:

Indukcja odpowiedzi limfocytów T CD4+ typu Th1, wydzielających IFN-γ, który aktywuje makrofagi do zwalczania infekcji mykobakteryjnej¹⁴
Aktywacja limfocytów T CD8+, które przyczyniają się do ochrony przeciwko M. tuberculosis¹⁵
Indukcja wyszkolonej odporności (trained immunity) poprzez epigenetyczne przeprogramowanie komórek odporności wrodzonej¹⁷
Zapewnienie niespecyficznej ochrony przed innymi patogenami poprzez heterologiczną odporność limfocytów T i wyszkoloną odporność¹⁸

Szczepionka BCG jest najskuteczniejsza w zapobieganiu ciężkim postaciom gruźlicy u dzieci, takim jak zapalenie opon mózgowo-rdzeniowych na tle gruźliczym i postać prosówkowa gruźlicy.⁷ Jej skuteczność w zapobieganiu gruźlicy płuc u dorosłych jest zmienna, co wynika z ograniczeń mechanizmu jej działania, takich jak brak systemu sekrecji ESX-1²², ekspozycja na niegruźlicze mykobakterie²⁴ oraz standardowa droga podania.²⁶

Nowe kierunki badań nad szczepionkami BCG, takie jak rekombinowane szczepy BCG i szczepionki wielostadiowe, mają na celu przezwyciężenie tych ograniczeń i zapewnienie lepszej ochrony przeciwko gruźlicy.²⁸ Głębsze zrozumienie mechanizmu działania szczepionki BCG jest kluczowe dla opracowania skuteczniejszych strategii zapobiegania gruźlicy w przyszłości.

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Materiały źródłowe

#1 Bacillus Calmette Guerin – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK538185/
Bacillus Calmette-Guerin (BCG) is the live attenuated vaccine form of Mycobacterium bovis used to prevent tuberculosis and other mycobacterial infections. The vaccine was developed by Calmette and Guerin and was first administered to human beings in 1921. BCG is the only vaccine against tuberculosis. It is the most widely administered vaccine and usually a part of the routine newborn immunization schedule. BCG vaccine also offers protection against non-tuberculous mycobacterial infections like leprosy and Buruli ulcer. This activity reviews the mode of action of the BCG vaccine and highlights the role of the interprofessional team in educating patients about tuberculosis prevention. […] BCG vaccine is a fairly safe vaccine and it is not associated with severe complications. Prior to the mycobacterial infection, vaccine-induced or acquired naturally can protect against subsequent infection due to mycobacteria including tuberculosis. Protection against tuberculosis infection is usually due to the immune response to mycobacterial antigens. Prior contained latent infection with Mycobacterium tuberculosis can provide up to 80 percent protection against disease with subsequent exposure.
#2 BCG Vaccine
https://www.pediatriconcall.com/drugs/bcg-vaccine/309
It is the live, attenuated mycobacteria bacillus Calmette Guerin strain of M.bovis attenuated strain of tuberculous bacillus. It is a freeze-dried vaccine and used to prevent against the disseminated form of tuberculosis such as TBM and miliary TB. […] Prevention of disseminated, severe forms of tuberculosis. […] BCG vaccine should not be given to individuals with positive tuberculin test. […] A mild local reaction occurs following most intradermal BCG injections, over 1-2 months, and sometimes a shallow ulcer may occur. Exaggerated reactions like abscess and large ulcers result due to injection being administered too deeply. Minor regional adenitis is common. Disseminated BCG infection can occur in the immunocompromised. Anaphylaxis has been reported.
#3
https://link.springer.com/article/10.1007/s00281-020-00794-0
Mycobacterium tuberculosis remains the leading cause of death attributed to a single infectious organism. Bacillus Calmette-Guerin (BCG), the standard vaccine against M. tuberculosis, is thought to prevent only 5% of all vaccine-preventable deaths due to tuberculosis, thus an alternative vaccine is required. […] The efficacy of BCG varies from 0 to 80% in protecting against pulmonary TB. It is estimated that globally, BCG prevents only 5% of all vaccine-preventable deaths due to TB, the cruel irony being that BCG is least effective in the areas of the world where it is most needed. […] The derivation of BCG is a result of pathogenesis experiments carried out by Calmette and Guerin, who after 230 passages and 13 years declared the organism to be safe and protective against M. tuberculosis.
#4 BCG: the history and modern-day uses of the tuberculosis vaccine – Pharmaceutical Technology
https://www.pharmaceutical-technology.com/features/bcg-vaccine-history-modern-uses-tuberculosis/
In 1921, the Bacillus Calmette-Gurin (BCG) tuberculosis vaccine was first administered to a human. The vaccine was developed by French scientists Albert Calmette and Camille Gurin to protect against tuberculosis of the lungs, a leading cause of death in the early 1900s. […] The BCG vaccines mechanism in this indication is unclear, but the jab is believed to induce a local immune response that helps to fight tumours within the bladder. […] Over 20 clinical trials are currently taking place to investigate whether the BCG jab could be repurposed to protect against Covid-19, or reduce the risk of severe lung damage from the virus.
#5 BCG-induced trained immunity: history, mechanisms and potential applications | Journal of Translational Medicine | Full Text
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03944-8
The Bacillus Calmette-Gurin (BCG) vaccine was discovered a century ago and has since been clinically applicable. BCG can not only be used for the prevention of tuberculosis, but also has a non-specific protective effect on the human body called trained immunity that is mediated by innate immune cells such as monocytes, macrophages, and natural killer cells. Mechanisms of trained immunity include epigenetic reprogramming, metabolic reprogramming, and long-term protection mediated by hematopoietic stem cells. […] Although the specific mechanism of BCG prevention on diseases has not been fully clarified, the potential role of BCG deserves further exploration, which is of great significance for prevention and treatment of diseases. […] Bacillus Calmette-Gurin (BCG) vaccine is an attenuated strain of Mycobacterium bovis obtained by serial passage. Mycobacterium bovis was firstly isolated in 1908 by Albert Calmette and Camille Guri from a glycerol bile potato medium at the Pasteur Institute in Lille. From 1908 to 1921, they serially passaged the strain and obtained a low-virulence strain and finally found that the strain protects the body from attack by the virulent Mycobacterium tuberculosis, and named it as BCG. […] In this review, we summarized the history, mechanisms, and potential applications of BCG-induced trained immunity.
#6 BCG vaccine – Wikipedia
https://en.wikipedia.org/wiki/BCG_vaccine
The Bacillus Calmette-Gurin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB). In countries where tuberculosis or leprosy is common, one dose is recommended in healthy babies as soon after birth as possible. […] Rates of protection against tuberculosis infection vary widely and protection lasts up to 20 years. Among children, it prevents about 20% from getting infected and among those who do get infected, it protects half from developing disease. […] The main use of BCG is for vaccination against tuberculosis. BCG vaccination can cause a false positive Mantoux test. […] A 1994 systematic review found that BCG reduces the risk of getting tuberculosis by about 50%. […] A systematic review and meta-analysis conducted in 2014 demonstrated that the BCG vaccine reduced infections by 19-27% and reduced progression to active tuberculosis by 71%.
#7 BCG vaccination: An update on current Australian practices
https://www1.racgp.org.au/ajgp/2020/october/bcg-vaccination-an-update-on-current-australian-pr
There is wide variability in the reported efficacy of the BCG vaccine in preventing TB. This partly stems from the different outcomes used (TB disease versus TB infection as measured with an IGRA or a TST), and partly from the difference in efficacy between subgroups. […] The greatest benefit of BCG vaccination is in the prevention of severe disseminated disease in young children. […] Estimates of the efficacy of BCG vaccination in preventing adult pulmonary disease vary widely in different settings (0-80%), with an average protection rate of 50%. […] A meta-analysis of BCG trials showed a relative risk of 0.49 (95% confidence interval: 0.34, 0.64) for TB disease in those who had received the BCG vaccine. […] The BCG vaccine’s protective effect against TB meningitis and miliary TB is consistently estimated at between 70% and 90%. […] BCG vaccination has been shown to be highly cost effective for children in high-incidence TB settings. […] The BCG vaccine is a safe, effective and cost-effective method of preventing many TB-related deaths, especially in young children.
#8 BCG vaccine – Wikipedia
https://en.wikipedia.org/wiki/BCG_vaccine
BCG seems to have its greatest effect in preventing miliary tuberculosis or tuberculosis meningitis, so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible. […] The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for 15 years; however, its protective effect appears to vary according to geography and the lab in which the vaccine strain was grown.
#9 Tuberculosis (TB) – Infectious Diseases – MSD Manual Professional Edition
https://www.msdmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb
The BCG vaccine, made from an attenuated strain of M. bovis, is given to 80% of the world’s children, primarily in high-burden countries. Overall average efficacy is probably only 50%, but BCG clearly reduces the rate of extrathoracic TB in children, especially TB meningitis, and may prevent TB infection. Thus, it is considered worthwhile in high-burden regions. […] Although BCG vaccination often converts the TST, the reaction is usually smaller than the response to natural TB infection, and it usually wanes more quickly. The TST reaction due to BCG is rarely 15 mm, and 15 years after BCG administration, it is rarely 10 mm. The CDC recommends that all TST reactions in children who have had BCG be attributed to TB infection (and treated accordingly) because untreated latent infection can have serious complications. IGRAs are not influenced by BCG vaccination and should ideally be used in patients who have received BCG to be sure that the TST response is due to infection with M. tuberculosis.
#10 Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis | The BMJ
https://www.bmj.com/content/349/bmj.g4643
The recently developed T cell based interferon release assays (IGRA) can detect M tuberculosis infection and discriminate this from previous BCG vaccination and most non-tuberculous mycobacterial infections, allowing investigation of whether BCG protects against M tuberculosis infection. […] This systematic review shows that BCG vaccination can protect against M tuberculosis infection and consolidates the results from recent studies showing evidence of protection against infection. […] Our results support a paradigm shift in the understanding of how antimycobacterial vaccines (new and old) can work, from the view that BCG protects against disease but not against infection to one that it protects against infection itself. […] The observed protection against M tuberculosis infection was independent of the assay method used for measurement.
#11 Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis | The BMJ
https://www.bmj.com/content/349/bmj.g4643
Objectives To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon release assays (IGRA) in children. […] The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. […] BCG protects against M tuberculosis infection as well as progression from infection to disease. […] BCG vaccine has been the subject of numerous efficacy trials and epidemiological studies conducted over several decades. […] These trials indicate that BCG has 60-80% protective efficacy against severe forms of tuberculosis in children, particularly meningitis, and its efficacy against pulmonary diseases varies geographically.
#12 A century of BCG vaccination: Immune mechanisms, animal models, non-traditional routes and implications for COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC9459386/
Bacillus Calmette-Guerin (BCG) has been used as a vaccine against tuberculosis since 1921 and remains the only currently approved vaccine for this infection. […] The recent discovery that BCG protects against initial infection, and not just against progression from latent to active disease, has significant implications for ongoing research into the immune mechanisms that are relevant to generate a solid host defense against Mycobacterium tuberculosis (Mtb). […] A strength of the BCG vaccine is that it induces immune responses to a broad range of mycobacterial antigens and requires no additional adjuvants for this immunogenicity. […] The recent discovery based on an IFN- release assay (IGRA) that BCG protects against Mtb infection and not just progression from LTBI to TB disease has significant research implications as it proves that innate, adaptive as well as trained memory responses are all involved in BCG mediated protection.
#13 The double-sided effects of Mycobacterium Bovis bacillus CalmetteâGuÃ©rin vaccine | npj Vaccines
https://www.nature.com/articles/s41541-020-00278-0
Bacillus CalmetteGurin (BCG), the only vaccine proven to be effective against tuberculosis (TB), is the most commonly used vaccine globally. […] Although BCG was specifically developed as a vaccine for TB, numerous studies have shown that BCG has the ability to induce the so-called Non-Specific Effects (NSEs) that provide effective protection against other infectious diseases. […] Clinical evidence also suggests that BCG may be effective against infections caused by viral pathogens, such as respiratory syncytial virus, human papilloma virus, and herpes simplex virus. […] Remarkably, BCG can be used as an expression vector for recombinant antigens to develop novel vaccines for pathogenic bacteria and viruses, as well as for cancer immunotherapy. […] As a complex vaccine consisting live-attenuated mycobacterium, BCG causes local infection and immune activation at the site of administration, where resident monocytes, macrophages, and dendritic cells (DCs) interact with the bacillus.
#14 The double-sided effects of Mycobacterium Bovis bacillus CalmetteâGuÃ©rin vaccine | npj Vaccines
https://www.nature.com/articles/s41541-020-00278-0
BCG internalized by DCs can live up to 2 weeks inside these cells, triggering the upregulation of costimulatory molecules and the production of immune-polarizing cytokines. […] Activated DCs at the BCG inoculation site migrate to the draining lymph nodes, and subsequently secrete TNF-, IL-6, and IL-12 to activate both CD4+ and CD8+ T cells. […] This explains the increased sensitivity to TB in humans with IFN- mutations and in mice with IFN- gene disrupted. […] The role of humoral immunity in TB is often neglected. […] However, since recent studies have indicated that antibodies have a role in the protection against TB, there has been a growing research interest in determining their relevance to vaccine development. […] Several mechanisms by which BCG provides NSEs protection against respiratory infections have been a subject of active investigation.
#15 A century of BCG vaccination: Immune mechanisms, animal models, non-traditional routes and implications for COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC9459386/
BCG induced macrophage activation also has significant impact on the anti-mycobacterial immune response and studies in mice have shown that mycobacterial killing by macrophages can be observed as early as 7 days post-BCG vaccination, suggesting that a portion of macrophage effector functions may be independent of adaptive immunity. […] While the importance of CD4 T cells with Th1 or polyfunctional properties is well established, other properties or differentiated functions of CD4 T cells have also been implicated in the immune response to BCG vaccination. […] It is now generally accepted that CD8 T cells have a significant role in protective immunity against Mtb, and the failure of BCG to provide adequate and lifelong protection against TB may be related in part to the insufficient generation of a CD8 T cell response.
#16 A century of BCG vaccination: Immune mechanisms, animal models, non-traditional routes and implications for COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC9459386/
Several other types of unconventional T cells, including but not limited to T cells, Mucosal associated invariant T (MAIT) cells and CD1-restricted T cells, have been implicated in BCG induced immunity. […] Since Mtb is an intracellular organism, the focus on the humoral responses against it has been limited and systematic investigations into B cell and antibody contribution to BCG-induced protection have not been undertaken. […] The recent discovery that BCG protects against initial infection, and not just against progression from latent to active disease, has significant implications for ongoing research into the immune mechanisms that are relevant to generate a solid host defense against Mycobacterium tuberculosis (Mtb). […] BCG has immuno-modulatory effects that make it effective against central nervous and disseminated TB when administered at birth or to school age children, but has shown minimal or variable protection against adult pulmonary TB.
#17 BCG-induced trained immunity: history, mechanisms and potential applications | Journal of Translational Medicine | Full Text
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03944-8
Until 2011, studies had found that these nonspecific protective effects were mediated by innate immune cells such as monocytes (Mo), macrophages (M), natural killer cells (NK), dendritic cells (DC), and neutrophils. Netea MG et al. showed that innate immunity conferred immune memory to innate host defenses. The feature is called trained immunity. […] A 2012 study, which combined in vivo and in vitro experiments, demonstrated that a NOD2-mediated epigenetic change at the level of histone methylation (H3K4me3) is the mechanism through which BCG enhances innate immune responses. […] Epigenetic reprograming is one of the molecular mechanisms that induces the development of trained immunity. The different types of epigenetic modifications include DNA modifications, noncoding RNAs, histone modifications, and chromatin remodeling. […] Furthermore, epigenetic reprogramming is regulated by changes in immune cell metabolic flux. Trained immunity can play a long-term protective effect against infection, which is the result of interaction with hematopoietic stem cells.
#18 The double-sided effects of Mycobacterium Bovis bacillus CalmetteâGuÃ©rin vaccine | npj Vaccines
https://www.nature.com/articles/s41541-020-00278-0
The first mechanism, heterologous T-cell immunity is mediated by heterologous T-cell memory responses to provide cross-protection. […] The second mechanism, trained immunity relies on reprogramming of innate immune cells that confer non-specific immune memory to innate immune responses. […] Trained immunity is non-specific innate immune protection, formed by monocytes/macrophages and NK cells of the innate immune system, which responds more rapidly and strongly against secondary infections of different microorganisms. […] Epigenetic reprogramming of monocytes in infection or immune sites has been shown as one of the molecular mechanisms that induces trained immunity. […] BCG vaccination induces trained immunity of monocytes/macrophages, leading to increased epigenetic reprogramming and host defense capabilities.
#19 BCG-induced trained immunity: history, mechanisms and potential applications | Journal of Translational Medicine | Full Text
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03944-8
BCG vaccination induces histone modifications and epigenetic reprogramming in human monocytes at the promoter sites of genes encoding inflammatory cytokines such as TNF- and IL-6. […] Pro-inflammatory cytokines produced by cells, such as TNF-, IL-1 and IL-6 coordinate local and systemic inflammatory responses. […] The BCG has been used for prevention and treatment of tuberculosis for 100 years, but the effect of BCG varies from person to person. […] Therefore, early vaccination with BCG is beneficial to reducing the incidence of these diseases.
#20 How does the BCG vaccine against TB provide protection against lung viral infections? – Research Institute of the McGill University Health Centre – RI-MUHC
https://rimuhc.ca/-/how-does-the-bcg-vaccine-against-tb-provide-protection-against-lung-viral-infections
We were very excited to discover that BCG vaccination provided remarkable protection against IAV infection, explains first author Kim A. Tran, a PhD candidate in Prof. Divangahi’s lab. The reduction of viral burden was dependent on interactions between memory T cells and one of the key innate residential cells in the lung, cells called alveolar macrophages. This is a previously unknown mechanism of cross-protection that is mediated by BCG. It highlights a crosstalk between the adaptive and innate immune memory system that is happening early on in infection. […] Conventionally, vaccine design involves the identification of a perfect antigen that generates long-term T and B cell memory responses and provides protective immunity when the same pathogen is next encountered. In this study, the researchers demonstrated that in response to the BCG vaccine, effector memory T cells for the mycobacteria expanded not only in the circulatory system, but also migrated into the lung tissue. Upon infection by the influenza virus, these BCG-specific memory T cells can be activated and then train proximal innate immune cells (alveolar macrophages) in the lungs to limit influenza virus replication.
#21
https://link.springer.com/article/10.1007/s00281-020-00794-0
Mycobacterium tuberculosis remains the leading cause of death attributed to a single infectious organism. Bacillus Calmette-Guerin (BCG), the standard vaccine against M. tuberculosis, is thought to prevent only 5% of all vaccine-preventable deaths due to tuberculosis, thus an alternative vaccine is required. […] The efficacy of BCG varies from 0 to 80% in protecting against pulmonary TB. It is estimated that globally, BCG prevents only 5% of all vaccine-preventable deaths due to TB, the cruel irony being that BCG is least effective in the areas of the world where it is most needed. […] The derivation of BCG is a result of pathogenesis experiments carried out by Calmette and Guerin, who after 230 passages and 13 years declared the organism to be safe and protective against M. tuberculosis.
#22 A new approach for improving BCG | Institut Pasteur
https://www.pasteur.fr/en/home/press-area/press-documents/new-approach-improving-bcg
Scientists at the Institut Pasteur and their partners in the international TBVAC2020 consortium have just developed a tuberculosis vaccine candidate derived from conventional BCG. This vaccine candidate has higher efficacy, due to a heterologous system of protein secretion that increases the quality and magnitude of the immune responses to virulent strains of Mycobacterium tuberculosis the bacterium responsible for the disease. […] The BCG vaccine consists of an attenuated strain of Mycobacterium bovis, and is considered effective in children, although it does not provide sufficient protection for adults particularly against pulmonary tuberculosis, which is the most infectious form. […] During infection the bacterium uses a specialized secretion system known as ESX-1 to compromise the integrity of the vacuole membrane of the host cell in which it is enclosed. Subsequent rupture of this membrane brings the mycobacterial components into contact with the cytosol of host cell. This is the signal for triggering a series of innate immune responses contributing to the control of mycobacterial growth. Due to a deletion of a chromosomal region, BCG lacks the ESX-1 secretion system. Its protective action is therefore not based on this powerful cascade of innate immune responses.
#23 A new approach for improving BCG | Institut Pasteur
https://www.pasteur.fr/en/home/press-area/press-documents/new-approach-improving-bcg
By expressing the ESX-1 secretion system of Mycobacterium marinum, a low-virulence aquatic mycobacterium, they constructed a recombinant BCG strain able to induce the same type of immune response as M. tuberculosis. „The key mechanism is the contact established between the bacterial components and cytosol which is found inside the host cell. Conventional BCG remains imprisoned in a vacuole and does not communicate to any great extent with the host cell cytosol”, explained Roland Brosch. The innate and adaptive immune responses achieved with the new strain are qualitatively and quantitatively enhanced and result in improved recognition of mycobacterial antigens. The virulence of the strain produced in this way is also attenuated, which makes it a promising vaccine candidate. Mice vaccinated with this strain have shown better protection against subsequent infection by M. tuberculosis than mice vaccinated with conventional BCG. […] These results were published in Cell Reports, and offer new possibilities for the development of a more effective vaccine against the various pathologies caused by M. tuberculosis, in particular pulmonary tuberculosis in adults.
#24
https://link.springer.com/article/10.1007/s00281-020-00794-0
The most significant factor influencing BCG efficacy that is supported by data is exposure to non-tuberculous mycobacteria (NTM). […] There are two hypotheses proposed for the mechanism by which NTM exposure reduces BCG efficacy: masking and blocking. […] One implication of this for the development of novel vaccines is that a dominant blocking mechanism suggests that a new vaccine need only be as good as BCG to have measurable effect, as long as it is not blocked by prior sensitisation. […] BCG vaccination has been shown to alter the acetylation and methylation of innate immune genes, amplifying the response to subsequent stimulus. […] A recombinant BCG vaccine candidate in late preclinical development, BCG zmp1, demonstrates increased phagosome maturation and phagolysosmal fusion, aiding antigen presentation resulting in improved protection. […] A recombinant strain of BCG expressing ESX1 (BCG::ESX-1) is more protective than wild type BCG in mouse and guinea pig models, although this recombinant strain is more virulent.
#25 Oral Tolerance to Environmental Mycobacteria Interferes with Intradermal, but Not Pulmonary, Immunization against Tuberculosis | PLOS Pathogens
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005614
A large body of clinical and experimental evidence implicates host exposure to environmental mycobacteria (EM) as the cause of interference with BCG vaccine-induced immunity. […] We explore the mechanism by which EM interferes with parenteral immunization and propose oral tolerance as a mechanism for this interference. […] Our research helps define the mechanism of EM interference with BCG vaccination and indicates that pulmonary administration enhances the protective effects of the BCG vaccine, regardless of prior EM exposure. […] Chronic oral exposure to EM results in systemic tolerance against mycobacteria. This tolerance generates poor immunity in a subsequent intradermal BCG vaccination scenario, and could lead to variable vaccine efficacy. However, because systemic tolerance is not present in the airways of hosts, pulmonary immunization generates robust immunity and is protective against Mtb challenge.
#26 A century of BCG vaccination: Immune mechanisms, animal models, non-traditional routes and implications for COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC9459386/
BCG is typically administered via the intradermal route, raising questions about whether this could account for its apparent failure to generate long-lasting immunological memory in the lungs and the inconsistent level of protection against pulmonary tuberculosis in adults. […] Recent years have seen a resurgence of interest in the mucosal and intravenous delivery routes as they have been shown to induce a better immune response both in the systemic and mucosal compartments. […] Finally, we discuss the potential benefits of the ability of BCG to confer trained immunity in a non-specific manner by broadly stimulating a host immunity resulting in a generalized survival benefit in neonates and the elderly, while potentially offering benefits for the control of new and emerging infectious diseases such as COVID-19.
#27 New, Safer, TB Vaccine with BCG
https://www.genengnews.com/topics/infectious-diseases/new-safer-tb-vaccine-with-bcg-kill-switch-protects-mice-and-monkeys/
In macaque monkeys, the updated self-destructing BCG vaccine caused an even stronger immune response and better protection against TB than a standard intravenously administered BCG injection. […] âOur data indicate that this âkill-switchâ BCG strain induces greater CD4 T-cell responses in lungs and may provide even more robust protection than WT BCG in macaques,â the investigators further noted. Sterilizing immunity occurred in 6 of 8 macaques compared with 2 of 8 wild-type BCG-immunized macaques. Thus, a âkill-switchâ BCG strain provides additional safety and robust protection against Mtb infection. […] Flynn added, âThe live-attenuated form of the mycobacteria does not need to be alive for very long to provide outstanding protection and with this strain, there is essentially no chance for a vaccine-derived infection, even in an immunocompromised host.â […] âWe hope that this âkill switchâ BCG strain could limit safety concerns over intravenous vaccine administration and provide an option for a safer and more effective vaccination route for individuals who are immunocompromised,â Flynn said.
#28 Key advances in vaccine development for tuberculosisâsuccess and challenges | npj Vaccines
https://www.nature.com/articles/s41541-023-00750-7
The ineffectiveness of BCG against pulmonary TB has prompted many groups to design alternative vaccines to enhance or replace BCG. […] The best example of a live whole cell vaccine is BCG, which is an attenuated form of Mycobacterium bovis, a mycobacterial species that is closely related to M. tuberculosis. BCG has many advantages as a vaccine. As it is genetically related to M. tuberculosis, its antigens are conserved. […] The safety record and clinical familiarity of BCG has prompted development of recombinant BCG strains to improve the immune responses elicited by vaccination. […] These changes in BCG elicit stronger CD4 and CD8 T cell responses in both preclinical and clinical settings. […] The compelling evidence that BCG can induce sterilizing immunity challenges the notion that the inconsistent efficacy of BCG vaccination in preventing pulmonary TB is attributable to BCG itself.
#29
https://link.springer.com/article/10.1007/s10096-016-2579-y
Mycobacterium bovis Bacillus Calmette-Gurin (BCG), an attenuated vaccine derived from M. bovis, is the only licensed vaccine against tuberculosis (TB). […] Genetic manipulation facilitates the construction of recombinant BCG (rBCG) vaccine that can be used as a highly immunogenic vaccine against TB with an improved safety profile, but, still, the manipulation of BCG vaccine to improve efficacy should be carefully considered, as it can bring in both favourable and unfavourable effects. […] The purpose of this review is not to comprehensively review the interaction between microorganisms and host cells in order to use rBCG expressing M. tuberculosis (Mtb) immunodominant antigens that are available in the public domain, but, rather, to also discuss the limitations of rBCG vaccine, expressing heterologous antigens, during manipulation that pave the way for a promising new vaccine approach.
#30 New, Safer, TB Vaccine with BCG
https://www.genengnews.com/topics/infectious-diseases/new-safer-tb-vaccine-with-bcg-kill-switch-protects-mice-and-monkeys/
Researchers headed by a team at Pitt University, in collaboration with scientists at Cornell University, have developed a self-destructing, intravenous (i.v.) Bacillus Calmette-GuÃ©rin (BCG) vaccine that in preclinical tests provided additional safety and protection against tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) in macaque monkeys. […] The in-built safety mechanismâa BCG âkill switchââin the live, attenuated Mycobacterium bovis strain circumvents the possibility of accidental self-infection with the weakened mycobacteria, which the developers say offers a safe and effective way to combat TB. […] Flynn is senior author of the teamâs published paper in Nature Microbiology, titled, âA BCG kill switch strain protects against Mycobacterium tuberculosis in mice and non-human primates with improved safety and immunogenicity.â In their paper, the researchers concluded: âUsing a self-killing BCG strain may increase the safety of i.v. BCG vaccination strategies while maintaining remarkable protective efficacy.â
#31 Protection against Mycobacterium tuberculosis Infection Offered by a New Multistage Subunit Vaccine Correlates with Increased Number of IFN-Î³+IL-2+ CD4+ and IFN-Î³+ CD8+ T Cells | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122560
Protein subunit vaccines present a compelling new area of research for control of tuberculosis (TB). Based on the interaction between Mycobacterium tuberculosis and its host, five stage-specific antigens of M. tuberculosis that participate in TB pathogenesis Rv1813, Rv2660c, Ag85B, Rv2623, and HspX were selected. […] The pathogenesis of M. tuberculosis progresses successively through primary infection, latency, and reactivation. During these infection stages, the metabolism and gene transcriptional profiles of M. tuberculosis show significant differences and stage-specific features in vivo. […] Although the BCG vaccine confers the CD4+ Th1 response and protects effectively against serious forms of TB during childhood, the protective efficacy gradually decreases over time and does not protect against pulmonary TB in adults or against reactivation from LTBI.
#32
https://www.jci.org/articles/view/46252
It is estimated that one-third of the worlds population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Gurin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. […] Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress-induced antigen Rv2660c. […] Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56.
#33 Protection against Mycobacterium tuberculosis Infection Offered by a New Multistage Subunit Vaccine Correlates with Increased Number of IFN-Î³+IL-2+ CD4+ and IFN-Î³+ CD8+ T Cells | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122560
The observations of the present study suggest that vaccination with A1D4/MTO, consisting of four antigens related to the phase of latency and one secreted antigen related to the phase of primary infection, could provide effective protection against M. tuberculosis infection in vaccinated mice and present an effective strategy for the development of the next generation of vaccines.