My last few blog posts discussed non-specific protection effects by live attenuated vaccines. You may be thinking: if live attenuated vaccines have such properties, can we just take any randomly-chosen live attenuated vaccine (e.g. BCG, OPV, or MMR) for COVID-19 prevention? Why should we bother to test these long-existing and widely-used vaccines before we use them as prophylaxis for COVID-19? Well, there are specific characteristics of the innate immunity system that enable the live attenuated vaccines to provide non-specific protection effects. Let us learn about this "trained innate immunity" today.1,2
Specific protective effect is attained in adaptive immunity level
You may still remember what you learned from secondary school that vaccines are a harmless forms of virus or bacteria (either killed, greatly weakened, or broken down into small parts) that stimulate the production of neutralizing antibodies that can recognize and bind specifically to the surface structure of the pathogen. Once these antibodies are produced, they are maintained at a low level in the body for the rest of the person's life, so that, should the real pathogen invade, the antibodies can recognize it immediately and trigger the concomitant killing process in a very short time. Neutralizing antibodies are a major part of the adaptive immune system and confer the memory characteristic of this immune system. Therefore, the specific protective effect conferred by a vaccine, including the live attenuated vaccine, is achieved via the adaptive immune system.
Non-specific protective effect is initiated via trained innate immunity
Live attenuated vaccines, such as the BCG, OPV, MMR and measles vaccines, however, also exhibit a broader range of protection which can exist for half a year to 5 years. This non-specificity does not involve the specific priming, and so it is not the result of adaptive immunity. Recently, scientists started to realize that vaccines trigger an immune response, which involves a diversity of cells belonging to the innate immune system, to provide a broader range of protection.1 The cells of the innate immunity may be primed upon encounter with the live attenuated vaccine, acquiring resistance to a second infection against the same pathogen, or unrelated pathogens with similar molecular patterns associated to the target pathogen. This is the basis of the "trained innate immunity". 1,2,3
The mechanism of how the innate immunity is being trained by live attenuated vaccines and attains a memory characteristic to react against invading pathogens with similar molecular patterns is not yet fully understood. However, as we can see from the evidence mentioned in my previous blog posts, different live attenuated vaccines induced different trained immunity programmes. For example, vaccination with the BCG vaccine can protect animals against secondary infection with Candida albicans and Schistosoma manasoni,4,5 but the other live attenuated vaccines do not have such heterologous protection effects against these pathogens.
Therefore, when we consider making use of the non-specific protection effects of a live attenuated vaccine for preventing COVID-19, it is important to test if the vaccine also works for the disease.
The molecular mechanisms leading to the trained innate immunity
Although the mechanism of how the trained immunity is attained is not fully understood, scientists have found that it involves multiple regulatory layers at the molecular level. This include changes in chromatin organization, transcription of long non-coding RNAs (lncRNAs), DNA methylation, etc. As the change in the chromatin level that alters gene expression is a relatively long-lasting process, this explains how innate immunity cells display a memory function and are thus able to react spontaneously upon the second infection.3
Moreover, recent work has found that haematopoietic stem cells, the progenitor of innate immune cells, also display a memory function. This solves the question of how the innate immune cells such as myeloid cells, with short-lived and an average half-life of 5-7 days, can display a memory function that can be maintained for several months or even years.3
Based on the above findings, we can understand that the heterologous protection against infections induced by live attenuated vaccine is reversible and can last for up to 5 years but is not retained for a whole lifetime.6 However, the duration of the protection varies with the vaccine used and with the pathogen that stimulate the non-specific effects. Therefore, it is important also for a clinical trial to find out how long the live attenuated vaccine can provide the non-specific protection against COVID-19, if the vaccine proved to be efficient against the disease.
What are the benefits from knowing more about the nature of trained immunity?
As trained immunity is initiated via the changes in DNA methylation, examination of the DNA's methylation patterns can provide clues to determine whether people are able to undergo trained immunity to stimuli by vaccination of a live attenuated vaccine. The identification of the genes which are differentially methylated in people who respond to the vaccine versus in people who do not respond, could potentially be used as predictors of responsiveness to stimuli that induce trained immunity.7
* The references cited is based on the review paper "Defining trained immunity and its role in health and disease" written by M.G. Netea, et al.
References
1. M.G. Netea, L.A.B. Joosten LA, E. Latz, et al. Trained immunity: a program of innate immune memory in health and disease. Science, 2016, 352 (6284): aaf1098.
2. M.G. Netea, J. Quintin, and J.W.M. van der Meer. Trained immunity: a memory for innate host defense. Review. Cell Host Microbe., 2011, May 19;9(5): 355-361.
3. M.G. Netea, J. Dominguez-Andres, L.B. Barreiro, et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol., 2020, Jun;20(6): 375-388.
4. J.W. van't Wout, R. Poell, and R. van Furth. The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand. J. Immunol., 1992, 36, 713-719.
5. J. Tribouley, J. Tribouley-Duret, and M. Appriou. Effect of Bacillus Callmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni. C. R. Seances Soc. Biol. Fil., 1978, 172, 902-904.
6. V. Nankabirwa, J.K. Tumwine, P.M. Mugaba, et al. Child survival and BCG vaccination: a community based prospective cohort study in Uganda. BMC Public Health, 2015, 15, 175.
7. J. Das, D. Verma, M. Gustafsson, et al. Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naïve subjects. Epigenetics, 2019, 14, 589-601.
Specific protective effect is attained in adaptive immunity level
You may still remember what you learned from secondary school that vaccines are a harmless forms of virus or bacteria (either killed, greatly weakened, or broken down into small parts) that stimulate the production of neutralizing antibodies that can recognize and bind specifically to the surface structure of the pathogen. Once these antibodies are produced, they are maintained at a low level in the body for the rest of the person's life, so that, should the real pathogen invade, the antibodies can recognize it immediately and trigger the concomitant killing process in a very short time. Neutralizing antibodies are a major part of the adaptive immune system and confer the memory characteristic of this immune system. Therefore, the specific protective effect conferred by a vaccine, including the live attenuated vaccine, is achieved via the adaptive immune system.
Non-specific protective effect is initiated via trained innate immunity
Live attenuated vaccines, such as the BCG, OPV, MMR and measles vaccines, however, also exhibit a broader range of protection which can exist for half a year to 5 years. This non-specificity does not involve the specific priming, and so it is not the result of adaptive immunity. Recently, scientists started to realize that vaccines trigger an immune response, which involves a diversity of cells belonging to the innate immune system, to provide a broader range of protection.1 The cells of the innate immunity may be primed upon encounter with the live attenuated vaccine, acquiring resistance to a second infection against the same pathogen, or unrelated pathogens with similar molecular patterns associated to the target pathogen. This is the basis of the "trained innate immunity". 1,2,3
The mechanism of how the innate immunity is being trained by live attenuated vaccines and attains a memory characteristic to react against invading pathogens with similar molecular patterns is not yet fully understood. However, as we can see from the evidence mentioned in my previous blog posts, different live attenuated vaccines induced different trained immunity programmes. For example, vaccination with the BCG vaccine can protect animals against secondary infection with Candida albicans and Schistosoma manasoni,4,5 but the other live attenuated vaccines do not have such heterologous protection effects against these pathogens.
Therefore, when we consider making use of the non-specific protection effects of a live attenuated vaccine for preventing COVID-19, it is important to test if the vaccine also works for the disease.
The molecular mechanisms leading to the trained innate immunity
Although the mechanism of how the trained immunity is attained is not fully understood, scientists have found that it involves multiple regulatory layers at the molecular level. This include changes in chromatin organization, transcription of long non-coding RNAs (lncRNAs), DNA methylation, etc. As the change in the chromatin level that alters gene expression is a relatively long-lasting process, this explains how innate immunity cells display a memory function and are thus able to react spontaneously upon the second infection.3
Moreover, recent work has found that haematopoietic stem cells, the progenitor of innate immune cells, also display a memory function. This solves the question of how the innate immune cells such as myeloid cells, with short-lived and an average half-life of 5-7 days, can display a memory function that can be maintained for several months or even years.3
Based on the above findings, we can understand that the heterologous protection against infections induced by live attenuated vaccine is reversible and can last for up to 5 years but is not retained for a whole lifetime.6 However, the duration of the protection varies with the vaccine used and with the pathogen that stimulate the non-specific effects. Therefore, it is important also for a clinical trial to find out how long the live attenuated vaccine can provide the non-specific protection against COVID-19, if the vaccine proved to be efficient against the disease.
What are the benefits from knowing more about the nature of trained immunity?
As trained immunity is initiated via the changes in DNA methylation, examination of the DNA's methylation patterns can provide clues to determine whether people are able to undergo trained immunity to stimuli by vaccination of a live attenuated vaccine. The identification of the genes which are differentially methylated in people who respond to the vaccine versus in people who do not respond, could potentially be used as predictors of responsiveness to stimuli that induce trained immunity.7
* The references cited is based on the review paper "Defining trained immunity and its role in health and disease" written by M.G. Netea, et al.
References
1. M.G. Netea, L.A.B. Joosten LA, E. Latz, et al. Trained immunity: a program of innate immune memory in health and disease. Science, 2016, 352 (6284): aaf1098.
2. M.G. Netea, J. Quintin, and J.W.M. van der Meer. Trained immunity: a memory for innate host defense. Review. Cell Host Microbe., 2011, May 19;9(5): 355-361.
3. M.G. Netea, J. Dominguez-Andres, L.B. Barreiro, et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol., 2020, Jun;20(6): 375-388.
4. J.W. van't Wout, R. Poell, and R. van Furth. The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand. J. Immunol., 1992, 36, 713-719.
5. J. Tribouley, J. Tribouley-Duret, and M. Appriou. Effect of Bacillus Callmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni. C. R. Seances Soc. Biol. Fil., 1978, 172, 902-904.
6. V. Nankabirwa, J.K. Tumwine, P.M. Mugaba, et al. Child survival and BCG vaccination: a community based prospective cohort study in Uganda. BMC Public Health, 2015, 15, 175.
7. J. Das, D. Verma, M. Gustafsson, et al. Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naïve subjects. Epigenetics, 2019, 14, 589-601.
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