How vaccines work ?
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A query of minds, this ppt focus on how vaccines induces protective response with help of B cell & T cell. The slides giving notes and detail r hidden
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How vaccines work ?
- 1. How Vaccines Work ? Dr. Vikram Gupta Immunology of Vaccination
- 2. How Vaccines Work? Dr. Vikram Gupta Assistant Professor, Department of Community Medicine, Dayanand Medical College & Hospital, Ludhiana dr_vikramgupta@yahoo.co.in
- 3. Agenda • How do vaccines work? Which are the main effectors of vaccine responses? • How Vaccine responses are elicited, supported, maintained and/or reactivated by vaccine antigens
- 4. Innate and Adaptive immunity
- 6. First steps after immunization
- 7. • So in case of deltoid injection draining lymphnodes will be axillary group and in case of quadriceps it will be inguinal group of lymph nodes.
- 9. Non-live vaccines • No microbial replication at site of injection so vaccine- induced activation of dendritic cells (DC’s) is limited, both in time and space. • Immunogenicity of non live vaccines is limited • Site and route of administration is important • Simultaneous administration of several distinct vaccines may take place without immune interference. • DCs are numerous in the well-vascularized muscles, which is the preferred route of injection for most vaccines. • Dendritic cells are in highest number in the skin – this allows a marked reduction (e.g. 10 fold) of the antigen dose in intradermal immunization, an advantage that is applied to the prevention of rabies in many countries.
- 10. Live vaccines • Replicate, disseminate and activate dendritic cells at multiple sites launching multiple foci of T and B cell activation • Immunogenicity of live vaccines is higher • Site and route of administration is unimportant • Simultaneous administration- Immune interference may occur unless they are given on the same day or if the routes of administration are different (eg OPV with other live vaccines
- 15. • These plasma cells migrate towards the red pulp of the spleen where they survive for a few weeks / months, secreting low levels of low affinity IgM, IgG or IgA antibodies. • As PS (polysachharide) antigens do not induce germinal centres, bona fide memory B cells are not elicited. Consequently, subsequent re-exposure to the same PS results into a repeat primary response that follows the same kinetics in previously vaccinated as in naïve individuals. • Revaccination with certain bacterial PS - of which group C meningococcus is a prototype - may even induce lower antibody responses than the first immunization, a phenomenon referred to as hyporesponsiveness and whose molecular and cellular basis is not yet fully understood.
- 24. What affects primary vaccine antibody responses? • Vaccine types: Live vs inactivated , Protein vs PS, Adjuvants • Antigen dose: Higher the dose-higher primary response. • Vaccine Schedule: 4 weeks minimum interval between primary doses avoids interference • Genetic, Environmental factors , Age
- 25. What controls persistence of Vaccine antibody responses? • Nature of vaccine- only live vaccine induces long lasting antibody resonse, shortest response by PS antigens • Vaccine schedules- Interval between primary doses, Interval before boosting • Age at immunization -shorter at two extremes of age • Disease conditions
- 26. Hallmarks of B cell memory responses? • Memory B cells do not protect • Reactivation occurs in response to natural boosters by pathogens or booster immunization • On reactivation antibodies appear in blood very rapidly (4-7 days) as proliferation and differentiation occurs without requiring development of Germinal center • Antibodies are of markedly higher affinity ( they can be only induced when sufficient time has passed after priming)
- 30. Immune Memory – implications for immunization programs • Immunization schedule should never be started “all over again” regardless of duration of interruption • Regular boosters are not required to maintain immune memory during low risk periods (Travellers) • Certain immunization schedules may not need boosters if exposure provides regular natural boosters • Booster may not be needed where reactivation of immune memory by offending pathogen is sufficiently rapid and effective to interrupt microbial invasion (Hep B)
- 31. Vaccine catch-up rules 1. Count the number of vaccine doses that are necessary for protection – separately for each antigen 2. Substract doses received = missing doses ! 3. Do not give more doses than an unimmunized child would receive ! 4. Choose the optimal intervals between missing doses • Baseline rule : 0 – 1 – 6 months (i.e. 6 month interval) • All missing vaccines may be given on the same day – at distant sites (>2.5cm) ! • All missing vaccines may be given at any interval (days, weeks) … •Except 2 live viral vaccines : 0 or 4 weeks (…)
- 32. • Since vaccination induces immunological memory the vaccination schedule need not be started all over again. Only the remaining doses need to be given. • For live viral vaccines, they should be either given on the same day or after 4 weeks to prevent immunologic interference. Exceptions are 1.BCG and measles/ MMR should not be given on the same day as measles depresses CMI that interferes with uptake of BCG. 2.OPV may be given at any interval from any live vaccine because the route of administration is different
- 33. Young Age Immunization 1. Young age limits antibody responses to most vaccine antigens: Why ? • Maternal antibodies inhibits antibodies responses but not T-Cell response • Limitation of B cell responses 2. Induction of B memory cells is not limited 3. Antibody responses elicited in early life are short lasting
- 36. Strategies • So what are the strategies to overcome these shortcomings during early infancy? • We give more doses or give vaccine at later age? • It is not possible to give vaccine late as most of these diseases occur at early age. • We give more doses of vaccines in comparison to adults and older children. • Age for starting vaccination and time interval depends on disease epidemiology.
- 37. Acknowledgement • This presentation is based on Science of Vaccinology Module of IAP and Advac Course . • International Vaccine Conference was held, by IAP at New Delhi in November 2008 and slides were part of resource material. Reference: 1. Siegrist CA : Vaccine Immunology . In:Vaccines.5th edition .Elsevier.2007 ,2,20-34.
- 38. THANX….
Editor's Notes
- My topic is Immunology – How Vaccines Work ? Immunology of Vaccination ?
- So we will discuss how do vaccines work? Which are the main effectors of vaccine responses? We will also see how Vaccine responses are elicited ,supported, maintained and reactivated by vaccine antigens
- Innate immunity comes into play within hours of the entry of an infective agent. The components of the innate immune system comprise of epithelial and mucosal barriers, the antibacterial chemicals in these barriers, phagocytes (neutrophils, macrophages and NK cells) as well as complement. It is not very specific as it is trigerred by structures shared by different microbes instead of specific microbial antigens. There is no immune memory. It plays a very important role as it is the first line of defense. It also is the effector pathway of adaptive immunity. Adaptive immunity is trigerred by antigen presentation by the cells of the innate immune system. It takes time to develop. The two arms of adaptive immunity humoral immunity ( B lymphocyte mediated) and cell mediated immunity (T lymphocyte mediated). It has intense diversity and is capable of responding to millions of antigens and possesses immune memory. Innate immunity comes into play within hours of the entry of an infective agent. The components of the innate immune system comprise of epithelial and mucosal barriers, the antibacterial chemicals in these barriers, phagocytes (neutrophils, macrophages and NK cells) as well as complement. It is not very specific as it is trigerred by structures shared by different microbes instead of specific microbial antigens. There is no immune memory. It plays a very important role as it is the first line of defense. It also is the effector pathway of adaptive immunity. Adaptive immunity is trigerred by antigen presentation by the cells of the innate immune system. It takes time to develop. The two arms of adaptive immunity humoral immunity ( B lymphocyte mediated) and cell mediated immunity (T lymphocyte mediated). It has intense diversity and is capable of responding to millions of antigens and possesses immune memory. Innate and adaptive immunity are interlinked. The immune response to microbes stimulates the adaptive response and the adaptive response strengthens the innate immune response. Some of the effecter pathways of the adaptive immune response are components of the innate response eg complement. Characteristics Innate immunity Adaptive immunity Onset Immediate (hrs) Delayed (days) Specificity Structures shared by groups of microbes Microbial and non microbial antigens Diversity Limited Very large Memory None Yes Components Skin and epithelia Complement Neutrophils, macrophages, NK cells Lymphocytes Antibodies
- Most of the currently available vaccines provide protection through induction of B cells and production of antigen-specific antibodies . This is known as humoral immunity. Antibodies either neutralize the antigen or promote opsonophagocytosis which results in early reduction of pathogen load and clearance of extracellular pathogens. Another way vaccine provides protection is by induction of T cells which is known as cell mediated immunity.The role of cell mediated immunity in currently used vaccines (that have T cell dependent antigens) is mainly by supporting antibody protection. Other less common mechanisms by which cell mediated immunity works is by are cytotoxic CD8+ T lymphocytes* (CTL) that may limit the spread of infectious agents by recognizing and killing infected cells or secreting specific antiviral cytokines. Cellular immunity is essential for clearance of intracellular pathogens. BCG is the only currently used human vaccine for which there is conclusive evidence that T cells are the main effectors. However, there is indirect evidence that vaccine-induced T cells contribute to the protection conferred by other vaccines. Example is that of measles immunization in 6- month-old infants. These infants fail to raise antibody responses because of immune immaturity and/or the residual presence of inhibitory maternal antibodies, but generate significant IFN-γ producing CD4+ T cells.These children remain susceptible to measles infection, but are protected against severe disease and death, presumably because of the viral clearance capacity of their vaccine-induced T cell effectors. Thus, prevention of infection may only be achieved by vaccine-induced antibodies, whereas disease attenuation and protection against complications may be supported by T cells even in the absence of specific antibodies .
- Following injection (1), the vaccine antigens attract local and systemic dendritic cells, monocytes and neutrophils (2). These activated monocytes and dendritic cells (3) change their surface receptors and migrate along lymphatic vessels (4), to the draining lymph nodes (5) where the activation of T and B lymphocytes will take place.
- So in case of deltoid injection draining lymphnodes will be axillary group and in case of quadriceps it will be inguinal group of lymph nodes.
- There is no microbial replication at site of injection in case of non-live vaccines so vaccine-induced activation of dendritic cells (DC’s) remains more limited, both in time and space. This limited activation has the following implications The immunogenicity of non live vaccines is limited as compared to live vaccines. Site and route of administration is important. Route of administration for non-live vaccines is decided by number of DCs in the tissue. DCs are numerous in the well-vascularized muscles, which is the preferred route of injection for most vaccines. DCs are fewer in adipose tissues, such that subcutaneous injections may be less effective than intramuscular injections under conditions of limited immunogenicity, such as for adult immunization against hepatitis B. Dendritic cells are in highest number in the skin – this allows a marked reduction (e.g. 10 fold) of the antigen dose in intradermal immunization, an advantage that is applied to the prevention of rabies in many countries. Simultaneous administration of several distinct vaccines may take place without immune interference if vaccines are administered at sites draining into distinct lymph node areas.
- Conversely live vaccines replicate, disseminate and activate dendritic cells at multiple sites, which migrate towards the corresponding draining lymph nodes and launch multiple foci of T and B cell activation. This widespread activation has the following implications Higher immunogenicity of live versus non-live vaccines . Site and route of injection of live viral vaccines are of minor importance: for example, the immunogenicity and reactogenicity of measles vaccine is similar following intramuscular or subcutaneous injection. Immune interference may occur unless they are given on the same day or if the routes of administration are different (eg OPV with other live vaccines)
- Now we will see what are the vaccine responses to polysaccharide antigens. This antigen released from the injection site essentially reach the marginal zone of the spleen / lymph nodes.
- B cells use their specific Ig surface receptors to bind to the repetitive structures of polysaccharides.
- In the absence of antigen-specific T cell help, B cells are activated, proliferate and differentiate in plasma cells without undergoing affinity maturation in germinal centers.
- These plasma cells migrate towards the red pulp of the spleen where they survive for a few weeks / months, secreting low levels of low affinity IgM, IgG or IgA antibodies.
- As PS antigens do not induce germinal centres, bona fide memory B cells are not elicited. Consequently, subsequent re-exposure to the same PS results into a repeat primary response that follows the same kinetics in previously vaccinated as in naïve individuals. Revaccination with certain bacterial PS - of which group C meningococcus is a prototype - may even induce lower antibody responses than the first immunization, a phenomenon referred to as hyporesponsiveness and whose molecular and cellular basis is not yet fully understood.
- In response to a protein antigen reaching lymph nodes or spleen. Extrafollicular reaction is same as in case of PS antigen , B cells rapidly differentiate in plasma cells that produce low-affinity antibodies (of the IgM +/- IgG/IgA isotypes) that appear at low levels in the serum within a few days after immunization . DC: dendritic cells APC: antigen presenting cells
- Antigen-specific helper T cells that have been activated by antigen-bearing dendritic cells trigger some antigen-specific B cells to migrate towards follicular dendritic cells (FDCs) , initiating the germinal center (GC) reaction.
- In GCs, B cells receive additional signals from follicular T cells (Tfh) and undergo massive clonal proliferation, switch from IgM towards IgG, IgA or IgE, undergo affinity maturation and differentiate into plasma cells secreting large amounts of antigen-specific antibodies.
- Most of the plasma cells die at the end of germinal centre reaction and thus a decline in antibody production and thus decline in antibody levels is noted 4-8 weeks after vaccination.
- However a few plasma cells exit nodes/spleen and migrate to survival niches mostly located in the bone marrow, where they survive through signals provided by supporting stromal cells. This results in prolonged production of antibodies and persistence of antibodies in the serum.
- Memory B cells are generated in response to T-dependent antigens, during the GC reaction, in parallel to plasma cells. At their exit of GCs, these B cells do not differentiate into antibody secreting plasma cells but in memory B cells that transiently migrate through the blood towards the extrafollicular areas of spleen and nodes. They persist there as resting cells until re exposed to their specific antigens. Upon secondary antigen exposure, memory B cells readily proliferate and differentiate into plasma cells secreting large amounts of high-affinity antibodies that may be detected in the serum within a few days after boosting.
- All protein containing vaccines (T cell dependent vaccines) whether live or non live induce immunologic memory. Non protein containing vaccines (T cell independent vaccines) do not induce memory as explained earlier.
- Vaccine type o Live vs inactivated- Higher intensity of innate responses, higher antigen content following replication and more prolonged antigen persistence generally result into higher Ab responses to live than inactivated vaccines. o Protein vs polysaccharide Recruitment of T cell help and induction of GCs results into higher Ab responses to protein or glycoconjugate than to PS vaccines o Adjuvants Modulation of antigen delivery and persistence (depot or slow-release formulations) or enhancement of Th responses (immunomodulator) may support or limit Ab response Antigen dose. As a rule, higher Ag doses increase the availability of Ag for B / T cell binding and activation, as well as for association with FDCs. Vaccine schedule o Interval between doses A 4 week minimal interval between primary doses avoids competition between successive waves of primary responses. Genetic determinants. Environmental factors. Mostly yet identified. Age at immunization. Early life immune immaturity or age-associated immune senescence.
- Nature of vaccine plays a crucial role: only live attenuated viral vaccines induce antibody responses that persist for several decades, if not life long in absence of subsequent antigen exposure and reactivation of immune memory. Shortest response are seen with PS vaccines. Vaccine Schedules: Closely spaced (1-2 Weeks) primary vaccine doses may be administered when a rapid induction of protection is desirable e.g. prior to travel,However for better persistence of responses 1-2 months interval is required between primary doses. Antibody responses are shorter at two extremes of ages. Certain disease conditions also modify vaccine responses like malaria .
- Memory B cells do not produce antibodies unless re-exposed to antigen which drives their differentiation in to antibody producing plasma cells. Read from the slide.
- When the second exposure with the similar antigen occurs at a short interval from the first dose, it triggers off a second wave of primary response rather than a true boosting response. Due to this the antibody levels attained are not very high.
- When the second antigenic exposure after a long interval between two doses ( 4 months) then an exuberant booster response is elicited. This is due to affinity maturation of B cells that results in high levels of antibodies of high affinity.
- Since vaccination induces immunological memory the vaccination schedule need not be started all over again. Only the remaining doses need to be given. For live viral vaccines, they should be either given on the same day or after 4 weeks to prevent immunologic interference. Exceptions are BCG and measles/ MMR should not be given on the same day as measles depresses CMI that interferes with uptake of BCG. OPV may be given at any interval from any live vaccine because the route of administration is different
- So what are the strategies to overcome these shortcomings during early infancy? We give more doses or give vaccine at later age? It is not possible to give vaccine late as most of these diseases occur at early age. We give more doses of vaccines in comparision to adults and older children. Age for starting vaccination and time interval depends on disease epidemiology.