Vaccines induce memory responses that allow the generation of rapid and heightened immunity—once exposure to the corresponding infectious microbe occur. How do vaccines induce memory responses? They do so by tricking the immune system into thinking it is experiencing an infection caused by the corresponding live microbe.
Vaccines consist of either live (attenuated) or killed microbes, or microbial components. Live vaccines replicate within the vaccinated host without causing disease, and are known—among the different types of vaccines—to induce the most effective immune responses. A new study published last month (March 19, 2018) in the journal Nature Immunology identifies the immunological mechanisms responsible for the efficacy of live vaccines.
In contrast to killed vaccines, live vaccines contain metabolically active microbes, which produce a wide range of different molecules. The study (Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses), which focused on live bacterial vaccines, found that one of the molecules produced by live bacteria marks them as viable. The molecule, ribonucleic acid (RNA), binds a specific type of immune receptor known as Toll-like receptor 8 (TLR8).
TLR8 is expressed on the cell surface of monocytes and, once triggered by RNA binding, initiates an immunological chain reaction that eventually leads to the production of a robust antibody response. The chain reaction includes the involvement of a specialized type of immune cells known as follicular helper cells (TFH). TFH cells play a critical role in the differentiation of B cells into plasma cells, which are cellular factories for antibody production.
For the study, researchers used a cell culture system consisting of human immune cells to compare responses generated against different live and killed bacteria. They found that live bacteria elicited slightly altered immune responses within the innate immune system—however, while the changes within the innate immune system were moderate, the effects on the adaptive immune response, which is responsible for the production of antibodies and for long-term memory, were striking. The striking effects were due to the induction, by live bacteria, of large amounts of IL-12 produced by monocytes—IL-12 then drives naive CD4+ T cells to differentiate into TFH cells. The researchers obtained similar results with E. coli, Gram-positive bacteria and mycobacteria.
The researchers then used an animal model—domestic pigs—to confirm the results obtained in the cell culture system. They immunized domestic pigs with either a live or heat-killed Salmonella vaccine and found that the live vaccine induced robust TFH cell responses as well as robust antibody responses, whereas the heat-killed vaccine did not.
Finally, the researchers found that individuals carrying a TLR8 gene variant responded better to immunization with bacillus Calmette-Guérin (BCG), the live tuberculosis vaccine.
All together, the study findings support a model in which natural infection or vaccination with live attenuated vaccines activate myeloid cells via TLR8 to produce large amounts of IL-12, which in turn drive differentiation of TFH cells and subsequent activation of B cells. Activation of B cells, then, results in B cell memory responses. Thus, TLR8 acts as a key switch for protective immune responses.
Leif Erik Sander, the study’s principal investigator, said in a press release: “Our immune system responds differently to killed and live vaccines. This is caused by the detection of RNA within live microorganisms via TLR8, which in turn triggers protective immune responses. These results may enable us to develop new vaccines that will combine the safety of modern subunit vaccines with the high efficacy of live vaccines.”
Live(attenuated) vaccines are better essentially because they cause a series of events that leads to better antibody and b memory cell production leading to better immune responses. This got me to thinking whether vaccines can be designed to effect t cells in a similar positive manner. After all, the many different types of effector t cells such as cytotoxic and CD4 t cells are what help to kill off infections. Studies have shown that replication-deficient viral vectored vaccines lead to strong responses that fill the gaps in our defense in terms of T-cell inducing vaccines (1). There has been significant finding that show that it is possible to induce the required T cell response to an infection via vaccination. Researchers employing a malaria mice model demonstrated enhanced CD8+ responses and protective efficacy when using such a vaccine. The studies done and results shown indicate that it is a viable option to protect against pathogens by engaging the other arm of the adaptive immune system; T cells.
T cell have been associated with vaccines in terms of memory cells. According to a research (1), the T cells response from vaccine is similar to any other damaging infection where it goes through the process of immunity. From this process, TCM cells are made in the lymphoid organs and TEM cells are stationed at the peripheral tissues (1). This specifically is the role of vaccines is to protect the population against an infectious agent. In relationship to the article above, the success of live attenuated vaccines is to be applauded. The information of TLR8 should increase our knowledge on preforming different types of vaccinations. But what if an individual does not have the TLR8 expressed on the monocytes to provide the immunity? Usually, when an individual does not express something important as a sensor or receptor for immunity, a substitute should take its place or the individual would be immunocompromised.
1. https://www.ncbi.nlm.nih.gov/pubmed/12531640
The question of whether or not vaccines can be designed to effect T cells specifically as they are the cells to actually induce the killing of infected cells is a loaded one. We know that T-cell memory is crucial for long term immunity so vaccines must somehow upregulate the actions of memory T cells for them to be successful. I think the question is rather vaccines directly or indirectly effect T cells. There have been a few studies that display different steps of the response of vaccines lead up to T cell upregulation. One way found is that NK cells are activated once a vaccine is administered. Once NK cells are activated, they will proliferate as expected and active other components of the immune response. The natural immune response continues and the NK activity then leads to T cell recruit and most importantly memory cell formation.
https://www.ncbi.nlm.nih.gov/pubmed/29484187
(1)1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246649/
The two types of vaccine that need attention are live and Inactivated.
Live vaccines, also called attenuated, work by using a weakened form of the microbe that causes the disease. These microbes are not strong enough to cause the actual disease but introduce the immune system with the infection. After introduction of the infection, the immune system produces memory cells (B and T) that are available for a long time if not a lifetime. This prevents the disease the next time it occurs. Live vaccines can be used against many diseases such as smallpox, chickenpox, shingles and many more.
On the other hand, inactivated vaccines are heat killed microbes that are used to prevent diseases. These are not as strong as live so more doses are needed over some period of time depending on the vaccine. This period of heat killed microbe introduction to the immune system creates an ongoing immunity against diseases. Inactivated vaccines prevent various diseases such as the flu, polio, rabies and hepatitis A.
https://www.ncbi.nlm.nih.gov/pubmed/29624615
Hey Klomashvili1, this whole concept of live-attenuated vaccines is very simple, yet complex in the way it works. It is interesting how the microbe that causes disease is not completely deactivated, but instead degraded to a certain level to which it is still active, but too weak to cause disease in the individual receiving the vaccination. One thing that I still question is that what if the individual receiving the live-attenuated vaccination has an extremely weak immune system? Would this method work just as effectively or would it result in harm to that individual? This is a question I still don’t seem to grasp. Apart from my question, I liked the way you broke down when live-attenuated or inactivated vaccinations are preferred. I wanted to share with you a different and neat article that I came across that might possibly help you expand your knowledge more regarding live attenuated and inactivated influenza vaccinations. This article presents a study on the efficiency and interaction of both live-attenuated and inactivated influenza vaccines in young chickens. In this study, performance of pc4 live attenuated influenza vaccines (pc4-LAIV) and inactivated influenza vaccines (IIV) were compared in young chickens that were vaccinated at 1 day old. The results of this study presented that a single dose of pc4-LAIV presented a more efficient innate immune response than IIV. Pc4-LAIV failed to replicate within young chickens possibly due to an underdeveloped immune system, but stimulated a dynamic immune response to the virus exposure. I am curious to know if apart from the type of vaccination, if age plays a role on whether certain vaccinations should be provided in the live-attenuated form or in the inactivated form.
https://www.ncbi.nlm.nih.gov/pubmed/29624615
Live attenuated vaccines do result in a substantial effect on the adaptive immune system for the production of antibodies and long-term memory. A question that arises from this discovery is how early should the vaccination be administered to produce a more effective immune system response? This study tested age-dependent immune responses on chickens after avian coronavirus vaccination. The study used infectious bronchitis virus (IBV), which is an endemic disease of chickens on a group of varying ages of chickens. The study used three groups of chickens at different ages; one group was one day old, the second group seven days old and the third group at fourteen days old. The study concluded that the one-day-old chickens lacked the most vaccine-mediated protection from the IBV vaccination. Lower IgG antibody levels were observed in the one-day-old chickens as compared to the other groups. The findings of the experiment strongly support stopping the vaccination of chickens after hatching and waiting approximately sevens days post-hatch to vaccinate. This concept could also be used for further studies on the timeline of vaccination to produce the most effective immune response on human babies.
https://www.ncbi.nlm.nih.gov/pubmed/25910920
Since we see that live attenuated vaccines have a greater effect on the immune system, we should also consider their how effective they are in regulating the immune response they cause. This is where regulatory T cells come in. These cells protect the body from potential tissue damage that can occur from an uncontrolled immune response. If Treg cells are too high in frequency, they can lower the efficacy of the vaccine. In a study performed to determine the effects of a live attenuated vaccine on Treg cells, it was compared to the effects that other types of vaccines. These consisted of an inactive trivalent vaccine and a subunit vaccine. These two showed no significant effects, only minor changes. However, the live attenuated vaccine first caused a decrease in Treg frequencies. After 14 days passed, the frequency increased. This leads us to assume that this type of vaccine is more effective at lowering Treg levels so that the immune system can respond and then raising the levels again to suppress the response and prevent any damage. This further supports the greater effect of live attenuated vaccines.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489208/
In understanding that attenuated (live) vaccines assist the innate and adaptive immune system in having a better response to certain pathogens than heat-killed vaccines, due to the live-vaccine’s RNA binding with TLR8 in order to enhance the production of antigens and memory B-cells, I couldn’t help but to think as to whether or not there was a way to increase the production of antigens for the heat-killed vaccines? And are there extreme consequences to using attenuated vaccines, considering that some pathogens are highly fatal to the host. In the article linked below it is suggested that heat-killed M. vaccae vaccine’s components could be a useful alternative to using attenuated vaccines to protect against tuberculosis, since attenuated vaccines can mutate and regain vitality.
Prophylactic vaccines induce strong T cell response against chronic replicating viruses. T cells activate naïve CD4 and CD8 cells through various mechanisms. At the same time, the majority of effector T cells are eliminated while Effector-memory T cells (TEM) and Central-memory T-cells proliferate (TCM) and Tissue-resident memory T cells (TRM). Memory inflation is described as a durable increased magnitude of memory T cells. TEM cells populations increase with memory inflation, as well as CD8 production. At the same time, Cytomegalovirus-specific antibodies increase over time. CMV has been used as a vector in attenuated vaccines providing long-lasting protection in mice. The effectivity of CMV as a vector was also tested expressing simian immunodeficiency virus (SIV). Therefore, when memory inflation is provoked T cells are able to protect against chronic replicating viruses in a better way.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820320/
Vaccines are extremely critical when it comes to medical treatment advancement technology. When it comes to vaccine development, attenuated as well as killed vaccines are available although the live version is the most popular. Contrasting killed microbes, attenuated vaccines contain a live version of the microbe that can actively replicate without causing disease to the host. These active microbes produce a wide range of chemicals that are helpful in conducting both the innate and more prominent adaptive immune responses. The RNA from the live microbe works actively by binding the TLR8 receptor expressed on the cell surface, initiates a chain reaction that promotes TFH cell production, plays a critical role in B cell memory responses, and induces large amounts of IL-12 – naturally produced via antigenic stimulation. With the known factors and experimental conditions of attenuated vaccines, it does not shock me as to why and how these are more beneficial and used more frequently than its counterpart. It actually makes me wonder why killed microbe vaccines are still being used when live vaccines have been shown to work faster and more efficiently. This is something that I would love more insight on and possible clarification as to why using the killed option is still practiced.
Source: https://www.ncbi.nlm.nih.gov/pubmed/12531640
Pink Ivy,
I find your comment to be very interesting and insightful. To be honest, I was wondering the same thing. However, with additional research and some prior knowledge, I believe that killed microbe vaccines, in some way, can be more advantageous over attenuated vaccine. Although killed microbe vaccines can be “antigenically” less powerful and may require more than one booster, there have some significant pros. For instance, killed microbe vaccines pose no risk for the infectious agent to reproduce or regress back to a harmful form. Additionally, they are still being utilized for individuals who are either pregnant or immune compromised. Although many people are able to receive attenuated vaccines, there are some individuals whose internal systems may not be able to endure the killed microbe vaccine. I would also like to add that some individuals are not capable of receiving vaccines at all due to a variety of medical conditions. So, in these cases, these individuals count on the people around them to be vaccinated in hopes of never acquiring the illness. This is referred to as herd immunity; I believe around 95% of the people around the individual needs to be vaccinated in order to prevent getting the illness. I hope this helps.
https://www.ncbi.nlm.nih.gov/pubmed/28492063
To add to the usefulness of the attenuated vaccine in comparison to the killed vaccine, modifications to a live-attenuated vaccine can confur a stronger immunogenicity towards a particular pathogen. The RNA-dependent RNA-polymerase of encephalitis virus strain TC 38 was mutated and it was demonstrated to elicit a strong immune response response to the wild type virus. The question of the possibility of an attenuated vaccine converting back to the wild type always sounds a caution to researchers. In an in-vitro study all may seem well but the viability of the phenotypic mutant in a host is another question that researchers need to answer when choosing live-attenuated vaccines.
http://www.ncbi.nlm.nih.gov/pubmed/29593882
Toll-like receptors play a key role in the innate immune system and sense invading pathogens or endogenous damage signals. The role of human TLR8 was examined and was shown to enhance both humoral and cellular immune responses. Patients who carried TLR8 gene responded better to immunization with bacillus Calmette-Guérin. TLR8 agonists demonstrated the ability to increase the protective effect of vaccine formulation. I wonder what other applications does the human Toll-like receptor 8 function in vivo tuberculosis and other autoimmune diseases? A study examined the role of human TLR8 in the disease progression of experimental infection, as well as the benefits provided by a TLR8 agonist against Mycobacterium tuberculosis challenge in a human TLR8 transgenic mouse. These mouse models might help seek mechanisms underlying the role of TLR8 in future disease progression.
https://www.ncbi.nlm.nih.gov/pubmed/29416532
hi raven,
Your post was very informative to the point where it got me to think about other forms of vaccinations. After researching, I came across a paper that enlightened me on the topic. To date vaccines are painfully injected into the patient, whether it’s attenuated or not. However, the article referenced, mentions the discovery of noninvasive administration. This can be done orally, intranasal, and transcutaneous procedures. The remarkable about this type of vaccine is that it still is as effective as a traditional administration. It will use humoral and cellular responses to protect the body from bacterial, fungal, parasitic and viral infections. I’m interested in seeing the future of vaccination.
https://www.ncbi.nlm.nih.gov/pubmed/29624470
Live-attenuated and inactivated pathogens have been the main products for production of vaccines. However, recent studies have provided evidence that a new platform for vaccine production has emerged. Protein-based vaccines postulate a new way to present vaccines that are safer than traditional methods. Nevertheless, these vaccines are not as durable as the traditional methods. Protein-based vaccines contain adjuvants that allow for regulation of antigen dispersal and boost immunogenicity. Adjuvants perform their function through PRR agonists which adjust immune responses to the type of antigen presented. The article focused on using adjuvants to help increase durability of protein-based viruses, specifically, Ebola VLP. Combination of a certain adjuvant, polyILCL along with the vaccine showed IFN gamma T cell production increased, higher up-regulation of CXCR5, and lower amounts of VLC and polyILCL needed for protection when compared with CD8 T cells. Protein-based vaccines are starting to expand in the amount of diseases they can prevent. The continued research and expansion of a protein based vaccine could have a huge impact on the future of diseases that currently reside within humans. Many people have feared away from getting vaccinations and have become nesting grounds for diseases to continually replicate and spread. The use of a protein-based vaccine could persuade those to get vaccines and could lead to fewer cases of the targeted diseases annually. Further experimentation should be done on enhancing durability.
https://www.ncbi.nlm.nih.gov/pubmed/26870818