I m u n i s a t i o n lecture for dental students

1. I m u n i s a t i o nlecture for dental students ZLLM0421p – Medical Oral Microbiology Week 10 Ondřej Zahradníček

2. Immunisation – principle Immunisation is based on fortifying of specific humoral, less frequently also cell mediated immunity We can liken immunisation to a hungry man on a river bank. How to help him? We would catch him fish – he will be quickly saturated, but the fish will be quickly eaten. This is like passive immunisation: antibodies are put directly into the body, they have effect immediately, but it is a short-termed effect We learn him how to catch fish – he will be know how to feed himself „forever“, but before he will learn it, he will be hungry. This corresponds to active immunisation: antigen is put into the body, the body starts to produce its own antibodies, but they would not be available immediately Sometimes we combine both approaches: the passive immunisation solves the acute situation, the active one serves for long-term solution.

3. Passive immunisation Antibodies or serum containing antibodies are put into the organism directly Disadvantage: antibodies from an alien person are never the same, they are less effective and the body gets rid of them step by step (short term effect) Advantage: the organism is protected immediately. The disadvantage of short term effect may be eliminated by combination with active immunisation (e. g. in tetanus)

4. Possibilities of passive immunisation Non-specific sera made of blood of many donors they contain antibodies against many common diseases they also contain lots of unwanted components that is why the use is more and more disputed Specific antibodies – examples TEGA – against tetanus HEPAGA – against hepatitis B BOSEA – globulins against botulism GASEA – against gas gangrene

5. Active immunisation Active immunisation = vaccination: a vaccine containing antigen is injected into the body. The body is challenged, „provoked“ by antigen to make antibodies. Vaccination against TB – exception: the goal is not production of antibodies, but formation of cell mediated immunity. This is related with particular mechanisms in TB infection

6. Vaccines against bacterial infections I Vaccination by living bacteria is used at tuberculosis. The vaccination was performed just after birth. Overall reinoculation should not be performed: immunity is checked by so called tuberculin test (In case of already existing immunity, the revaccination might cause complications, e. g. an ulcer in the site of vaccination.) Bacterins – complete dead bacteria. For instance, the older (since 2007 mostly not used) type of a vaccine against whooping cough caused by Bordetella pertussis.

7. Vaccines against bacterial infections II Anatoxins or toxoids – used in situations, where bacteria have effect by their toxins (poisons). Anatoxin = a toxin that is no more toxic, but it still acts as an antigenic challenge. E. g. vaccination against tetanus and diphtheria. Subunit vaccines = purified surface antigens (e. g. polysaccharide), for instance new vaccination against whooping cough, vaccination against Haemophilus influenzae b, Neisseria meningitidis etc. At polysaccharide vaccine it is also an opportunity to make a conjugated vaccine by conjugation of a polysaccharide to a protein Recombinant vaccines are a particular case in the previous – a gene is „planted“ on another organism

8. Vaccines against viral infections Living vaccines –attenuated strains of viruses are cultured on the cell cultures. In immunocompromised persons they may cause various infections. Measles, mumps and rubella; also Sabin vaccine against polio (not commonly used today; it was a vaccine administered orally in order to mimic the natural portal of entrance and challenge of mucosal immunity). An inactivated virus. The virus is cultured, then killed, by heating or by chemical compounds. Examples: vaccination against influenza, rabies, hepatitis A Recombinant subunit vaccines are used in lots of viruses, e. g. in tick borne encephalitis, hepatitis B, influenza, polio (Salk vaccine) etc.

9. Regular vaccination They use to be refunded by state and are often obligatory (or just recommended, it depends on legal situation in different countries). In Czechia it contains recently nine illnesses, that are prevented according to „vaccination calendar“ (a hexavaccine, a trivaccine MMR + all revaccinations) Particular situation exists for vaccination against tuberculosis (since 2010 all children are not vaccinated, but the mothers are supposed to fill in a request form and in case of being in a „risky group“ she is obliged to contact so called „calmetisation station“, so this vaccine is still considered to be a regular vaccination)

10. Other vaccination Czech Order No. 537/2006 (in the recent version) recognizes not only regular vaccination, but also particular vaccination, extraordinary vaccination, vaccination at injuries and vaccination on request. Extraordinary vaccination might be eventually compulsory (at epidemic outbreaks). Czechia also has recommended vaccinations, that are not compulsory, but they are refunded – but not by the state, but from the patient‘s health insurance. It is vaccination against pneumococci for children and against cervical carcinoma in 13 years old girls

11. More vaccinations Vaccination at professional risk (hepatitis B or even influenza in healthcare staff, tick borne encephalitis in foresters) – employees have it often refunded by employers, sometimes it is even part of a legislature for given professional risk Vaccination for travellers (yellow fever, dengue, Japanese encephalitis…) Vaccination of immunucompromised people (influenza, pneumococcal vaccine in a hospital) Prophylactic vaccination (rabies, also tetanus) Vaccination on request (influenza, tick borne encephalitis)

12. Vaccination against TB A single vaccine (= not like tri- or hexavaccines) vaccination was usually performed in the first week after birth, now replaced by a request form (to check whether a person belongs to a risky group) It is also possible to get a child vaccinated on request Later a tuberculin examination is performed – a skin test of the cell mediated immunity. In case of negativity, revaccination is performed. Vaccination of already immune persons would be dangerous

13. Vaccination against TB www.indoindians.com/health/vaccine.htm Calmette-Guérin bacillus (from here the term „calmetisation“)

14. Vaccination against tetanus Vaccinated in combination with five other diseases Besides revaccination by the hexavaccine in the first year of life, another revaccination is recommended for 11–12 years old children by a trivaccine (classic „di-te-pe“), and in adult age usually by a single vaccine against tetanus only The vaccine is an anatoxin (toxin with no toxicity, but existing antigenic properties) Tetanus is not common today, but it is such a serious disease, that vaccination is still considered useful. Tetanic clostridia are also today in intestine of some animals and also in soil; there is a high risk for non-vaccinated people

15. Vaccination against diphtheriaand whooping cough Vaccinated in a combination Besides revaccination by the hexavaccine in the first year of life, another revaccination is recommended for 11–12 years old children by a trivaccine (classic „di-te-pe“), adults my be vaccinated on request together with tetanic vaccine Vaccine against diphtheria is an anatoxin, the one against whooping cough is a mixture of an anatoxin and other antigens Diphtheria is not present in Czechia recently, but it might be reintroduced. Whooping cough is on increase in last time.

16. Tetanus, diphtheria and pertussis Absolute numbers since 1945 diphtheria tetanus whooping cough Absolute numbers (log) Year Source:

17. Vaccination against „Hib“ This is a vaccination against Haemophilus influenzae, more precisely against encapsulated strains with capsular type b The vaccine is a conjugated vaccine Usually the vaccine is used as combination It was introduced several years ago and after its introduction the number of invasive haemophilus infections of pre-scholar children (meningitis, pneumonia, epiglottitis) significantly decreased

18. Invasive haemophilus infections Absolute numbers since 1980 Absolute numbers per year type B haemophilus infections Year Source:

19. Vaccination against „Hib“ – indications Conjugated haemophilus vaccine serves to vaccination of six weeks old children not vaccinated against TB eventually older than three months if the child was vaccinated against tuberculosis and the scare after that vaccination is completely healed Vaccination of adults is possible, if they are endangered by risk of complications of that disease and the producer does not limit its use for persons over five years (www.vakciny.net)

20. Available vaccines against Hib ACT-HIB (against Hib) INFANRIX HEXA (diphtheria, tetanus, whooping cough, Hib, hepatitis B and polio – dead virus), similar HEXACIMA INFANRIX-IPV+HIB (the same except VHB) INFANRIX HIB (the same except polio + VHB) Situation changes quickly, so do not take this as valid forever

21. Vaccination against hepatitis B Vaccination of children is a part of hexavaccine. Adults usually use a stand-alone vaccine, or a bivaccine for hepatitis A + B. The immunisation is performed using a recombinant vaccine prepared on the yeast Saccharomyces cerevisiae Another relatively newer vaccination – before becoming a regular vaccine it was only used for risky groups (e. g. children of HBsAg positive mothers) or in professional risk (health care professionals)

22. Vaccination against polio Since 2007/08 also Czechia started to use injections of Salk vaccine (dead virus) that enable combination with other vaccines (hexavaccine). Majority of other European countries implemented this vaccine already sooner. Revaccination in 10–11 years is a stand-alone vaccine Sooner, the orally administered Sabin vaccine was used– living virus. It is highly effective, but it has slightly higher risk of complications Polio – poliomyelitis is a disease considered eradicated in Europe, but worldwide eradication is still far from being accomplished. Also this it the reason why the vaccination proceeds in Czechia and other European countries

23. Salk and Sabin http://en.wikipedia.org/wiki/Image:Stamp-ctc-polio-vaccine.jpg http://www.hindu.com/seta

24. Vaccination against measles It is a part of trivaccine with mumps and rubella („MMR vaccine“), all three parts of it are living attenuated viruses These three vaccinations are often impugned (some people say „children may get infected, these are normal childhood diseases) In fact, measles are quite unpleasant disease with pain and fever, and causes economical loses (parents stay at home with the ill child) There exist also the risk of Subacute sclerosing panencephalitis,especially in adults. It it very rare, but also very serious disease.

25. Vaccination against rubella This vaccination started in 80‘s, first 12 year old girls and later also all two years old children were vaccinated (Czechia) Rubella, too, in period before vaccination caused big economical loss, complications for schools and kindergartens etc. Rubella is dangerous for pregnant women, there exist a risk of abortion of infected females. When a pregnant woman gets ill, the risk of damage of the foetus is 50 % in the first month of gravidity, 25 % in the second, 10 % in the third and only 5 % in the fourth and later

26. Vaccination against mumps Vaccination against mumps is performed in Czechia since 1987, most of the time together with measles and rubella While rubella is dangerous for pregnant women, mumps are rather dangerous for adult men: there exist a risk of orchitis (testicle inflammation) that may cause infertility Some vaccines against measles, rubella and mumps also contain a component against varicella.

27. Vaccination „MMR“ (measles, mumps, rubella) www.sciencemuseum.org.uk http://www.brown.edu/Courses/Bio_160/Projects2000/MMR/mmrmeaslesvaccine.htm

28. Measles, mumps and rubella Absolute numbers since 1955 measles mumps rubella Absolute numbers (log) Year Source:

29. Vaccination against influenza The vaccine is made of strains cultured on cell cultures (rather than fertilized eggs that were used before) In recent period it is more popular than sooner, because of their risk of so called avian influenza („bird flu“, H5N1) and later also „swine flu“ (H1N1) In case of influenza, we have to count with the antigenic drift (minor changes of the antigenic structure) and shift (bigger changes). That is why the vaccination does not leave a long term immunity and should be renewed every year

30. An example of a vaccine against influenza whyfiles.org/195bird_flu/4.html

31. Vaccination against TBE Vaccination against tick borne encephalitis is a commonly desired vaccination – but people often let the children vaccinated, although the disease is more serious in adults, especially seniors. Not recommended under 6 years (too big antigenic challenge for child organism at parallel vaccination by regular vaccines) Vaccination consists of two doses usually during winter and third, „booster“ dose follows the next winter. After three years revaccination is recommended. Obviously, it does not protect against Lyme disease; the vaccine against it is in development, but not in routine use.

32. Vaccination against pneumococcal infections Vaccination against pneumococci was first in Czechia that was „not compulsory, but free“ (refunded from the healthcare). Pneumococcal invasive infection may be dangerous and may leave permanent sequels, that is why this vaccine is quite recommendable. http://contanatura.net/arquivo/Streptococcus%20pneumoniae.jpg

33. Available vaccines Polysaccharide vaccine PNEUMO 23 (23 serotypes), suitable only for adults (e. g. in-patients that should be protected) Conjugated vaccines (longer immunity memory and better immunity response in persons with not sufficiently developed immunity, including children younger than two years) Prevenar (7 serotypes) Prevenar 13 (13 serotypes) Synflorix (10 serotypes + diphtheria, tetanus a whooping cough)

34. Because of low frequency of meningococcal invasive infections Czechia only vaccinates „indicated groups“ (people in military service, contacts with invasive infections) Also used as vaccination „on request“, especially at travelling abroad (but the serogroups typical for individual countries should be checked) Vaccination against meningococcal infections

35. www.baxter-ecommerce.com Vaccines • They are not the same – old polysaccharidic vaccines were worse than conjugated ones • Also difference in serogroups, effect may be against one or more of them (C, A + C or A + C + W135 + Y) • For non-travelling Europeans C or A + C is enough • On the other hand, for hajj for Mekka the tetravaccine is needed, because Arabian peninsula is inhabited by the serogroup W135 • Since 2014 the vaccine Bexsero is available against group B, effect is not sufficiently proven yet. Group B has poor immunogenity, that is why it was so difficult to prepare a vaccine

36. Various serogroups in the world http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/09vol35/acs-dcc-4/index-eng.php

37. Polysaccharides vaccines vs. conjugated vaccines • Even today, bivalent* or tetravalent** polysaccharide vaccines against meningococcal infections of group A and C or A, C, Y and W135. But the immunology memory is short for them • This problem was compensated by conjugated vaccines. Recently monovalent conjugated vaccines against meningococcal infections caused by group C are available. All these vaccines are highly immunogenous and safe. * = against two serogroups ** = against four serogroups

38. Vaccination against human papilomavirus (HPV) Also known as „vaccination against cervical cancer“, because the goal is really mostly vaccination against strains of HPV, that are related to that cancer (only some types do) In Czechia, health insurance refunds vaccination of thirteen year old girls (the highest effectiveness is in girls before start of sexual life) There exist two most common vaccines – SILGARD, sometimes also known as GARDASIL, and CERVARIX

39. More vaccination Against varicella (1) Against various tropical diseases (yellow fever, Japanese encephalitis, cholera and various other – it depends on destination and intended behaviour) Against HIV (research) Vaccination against malaria is not yet available, although it is supposed to come soon; until now, so called chemoprophylaxis is recommended. The new vaccine also has probably low effect http://www.kimtran.net 1

40. Six basic rules for vaccination at travelling • 1. Risk – Vaccination should be done according to the risky behaviour of the traveller rather than only destination • 2. Combine effectively various types of vaccination (rule of three R-s: routine, requested, recommended) • Regular (do not forget the revaccination against tetanus) • Requested, compulsory for some countries (mostly yellow fever: compulsory not only for countries with risk of infection, but also for other countries; other countries usually have it compulsory just for people coming from endemic countries, what might be confusing. Vaccination against meningococcal infection is compulsory for people going to the hajj) • Recommended – according to the risk • 3. Basic vaccination schemes or booster • 4. Possible combinations – interferences, timing • 5. Application sites – not the same lymph nods, usually not gluteal region • 6. Time to departure – vaccination scheme should be adapted According to prof. Beran

41. Unwanted effects of vaccination If would be irresponsible to deny that vaccination may also have unwished effects It is even true that they may be cause of death (very rarely, under particular circumstances) The unwanted effect might be caused by allergy to one of components of a vaccine (not only antigen, but also helping agents) excitation of immunity system, especially in persons with diseased immunity in immunocompromised persons, when using living viruses and bacteria, even proper (week) disease may be seen

42. Are they a reason for not vaccinating? Thanks to vaccination people forget the time when people with active TB were walking on streets, that were a thread for the other people. The forgot to handicapped children after polio. Even apparently „innocent“ diseases, as mumps or rubella, may have difficult complications, risk for foetus or for man‘s fertility etc. On the contrary, existence of frequent of serious side effects of vaccines (e. g. autism) was never proven; all studies have shown that nothing like that exists in fact

43. Risk and benefit Each medical approach has certain risk of failure or unwanted effect That is why a very strict control exists from the side of the state (health ministry, state office for drug control, public health office…) and medical professional societies that disable use of „non lege artis“ procedures, that means „not in accordance with recent scientific knowledge“ All procedures supported by all these institutions have clearly higher benefit than risk On the other hand, there exist questions: whether to terminate vaccination against polio, or to wait; whether to let all regular vaccines as „compulsory“ whether to be rather restrictive, or rather explaining and convincing people

44. Vaccination rate and its importance • Vaccination rate is never 100 %: some children cannot be vaccinated because of medical reasons (immunity disorders etc.) • Usually decrease of vaccination rate e. g. from 95 % to 90 % has no negative effect • Nevertheless, at further decrease, there exist a risk of chain of unvaccinated persons  epidemic outbreak of the given disease (for instance measles outbreak in Germany 2013–2015, with died toddlers) vaccinated not vac-cinated

45. „It is my right to not vaccinate my child“. It is disputable. A child is not the ownership of the mother; if the mother would maltreat a child, she would be arrested). On the other hand, ca child is also not an ownership of the state In many diseases, it is not just question of „my child“, but also neighbour‘s child that might be infected from my (not vaccinated) child. The lower the vaccination rate is, the bigger is there a risk of outbreaks. Of course, this is only valid for diseases with high risk of person-to-person transmission (measles, but not tetanus or hepatitis B)

46. Compulsory vaccination: yes/not? In majority of West-European countries the vaccination is mostly recommended, but not compulsory On the other hand, in Czechia compulsory vaccination is a tradition, and even some „western“ experts would prefer the Czech system; it is also related with the recent outbreaks (measles in Germany) It is also a question of „compliance“. In some countries people let the children vaccinated, although it is „only recommended“ (difficult to say, whether it would be the same for Czechia) My recent personal point of view is rather yes with discussion for individual vaccines, and also „rather argument and not just restriction“

47. Another extreme There exist also another extreme: some people, influenced by advertisement, request vaccination, that is not suitable for them or for their children E. g. in young children, vaccination against tick borne encephalitis is not recommended, the children are guarded and the disease usually does not have a not serious course in children Let‘s believe authorities – if they recommend something (or they recommend not to use it) they use to have a good reason.

48. Thanks for attendance www.dep.anl.gov/S3A/antibody-puzzle.JPG