Immunity

Passive and Active Immunity

1. Sechenov First State Medical University, Moscow
Microbiology, Virology & Immunology Department
MEDICAL IMMUNOBIOLOGICAL PREPARATIONS
for ACTIVE and PASSIVE IMMUNITY
by Yelena V. Budanova
M.D., Associate Professor

2. ‘Never in the history of human progress has a
better and cheaper method of preventing illness
been developed than immunization at its best’
(Geoffrey Edsall, pathologist)

3. INTRODUCTION
•Immunity is the resistance of the
organism to invasion by microbe and
damage by foreign substance
•There are innate (=inherent) and acquired
immunity types
•Acquired immunity can be natural or artificial
•Both are divided into active and passive
•Adaptive immunity results when lymphoid cells
are transferred from another individual

4. Acquired immunity
Natural Artificial
Active Passive Active Passive
results from
natural
infection –
“post-
infectious”
immunity
follows by
passage of
maternal IgG
through
placenta or
transfer of IgA
from mother’s
breast milk or
colostrum
is due to
vaccination
is due to
introducing of
presynthesized
antibodies or
sensitized
lymphocytes
from another
individual or
animal

5. Immunization
•Immunization is the process
rendering a host immune
•It can be active (due to vaccination) or
passive
•Medical immune biological preparations (MIBP)
can help to make person immune
•Immune biological preparations
are biologically active substances
that can specifically effect immune
system

6. Immune biological preparations
•MIBP include:
 vaccines
immune antisera
immunoglobulins and
hyperimmune plasma
immunomodifiers
adaptogens

7. VACCINES
‘Prevention is better than cure’

8. VACCINES
•Vaccine is a preparation of microbes or
toxoids that can no longer induce disease
but can still stimulate active immunity
against the corresponding pathogen or its
toxin
•Vaccine is any preparation intended for active
immunological prophylaxis, preparation of killed microbes of
virulent strains or living microbes of attenuated (variant or
mutant) strains, or microbial, plant, metazoan or products
[Stedman's Concise Medical Dictionary]
•It is an antigen
•Vaccine can induce antibacterial, antiviral or
antitoxic immunity, or immunity against parasites
•Vaccine (latin “vacca” = cow, vaccinus=relating to a cow)

9. Variolation
•Variola = smallpox
•The ancient practice of ‘variolation’ dates back
to 10
th
century China and arrived in Europe in
the early 18
th
century
•Variolation is a technique involved inoculation
of children with dried material from healed
scabs of mild smallpox cases
•It was inconsistent and dangerous

10. Edward Jenner (1749-1823)
•The English physician
•The founder of modern
vaccination
•He has shown that more
reliable protection could be
obtained by inoculation with
cowpox (vaccinia) virus
•In 1796 E.Jenner tested his
theory by inoculating 8-year-
old boy

11. The first vaccination
•Milkmaids exposed to
cowpox virus were
traditionally resistant to
smallpox
•On the picture: E. Jenner
administers the first
vaccine to 8-year-old
James Phipps using pus
from a milkmaid’s cowpox
lesion
•This procedure protected
this child from smallpox
(he has been inoculated with
smallpox virus later)

12. •People naturally acquired
smallpox by exposure to the
smallpox virus shed from
persons with the disease. If a
person survived he/she
developed immunity to
disease
•The smallpox and cowpox
viruses have similar surface
antigens, so the vaccinated
person became immune to
both smallpox and cowpox

13. Louis Pasteur (1822-1895)
•A French Scientist known as a
founding father of Microbiology
•He has given a name “vaccine”
•He attenuated chicken cholera
pathogens to cause immunity
without inducing disease
•In 1881 he made a vaccine against
anthrax in domestic animals
•In 1885 he inoculated a 9-year-old
boy bitten by a rabid dog with
attenuated rabies vaccine made from
the dried spinal cord of infected
rabbits. A boy survived

14. VACCINATION
•Vaccination is the act of
administering vaccine by inoculating
it into the human body
•The principle of vaccination is simple:
to induce a “prime” state so that on first contact
with the relevant pathogen a RAPID and
EFFECTIVE SECONDARY IMMUNE RESPONSE
will be mounted leading to prevention of disease
•It is called the immunologic memory phenomenon

15. IMMUNOLOGIC MEMORY
•The main steps in the active immunity development:
Vaccine is inoculated by a shot or spray
Human organism makes antibodies and memory cells against the
antigen in the vaccine
Antibodies can fight the real disease if the person is exposed to the
pathogen
Antibodies and memory cells stay on guard in the body for years
after the vaccination

16. The Main Aims of Vaccination
•To prevent symptoms of the disease
•To block the pathogen transmission in a population
•To generate herd immunity (i.e., making a human
population immune)
•To eradicate the disease (the most ambitious )

17. •In the mid-1960-s, the WHO launched a programme to eradicate
smallpox
•It was the first and only absolute success against disease
•In October, 1977, the last naturally acquired smallpox was reported
•With the recovery of this patient from Somalia (pic.) smallpox was
eradicated from the Earth

18. Three Major Infectious Killers
organismorganism diseasedisease estimated annual estimated annual
deaths (millions)deaths (millions)
HIVHIV AIDSAIDS 2.62.6
Mycobacterium Mycobacterium
tuberculosistuberculosis
TuberculosisTuberculosis 1.51.5
Plasmodium sp.Plasmodium sp.MalariaMalaria 1.11.1
TOTAL 5.2TOTAL 5.2

19. The REQUIREMENTS for the EFFECTIVE VACCINE and
VACCINE STRAIN
•Protective effect (=high immunogenicity)
•Safety that includes:
low virulence
low side effects (=no complications)
low harm
low allergic effect (=low ‘reactogenic’)
low teratogenic and
low oncogenic effects
•Purity and stability of antigens
•Low cost

20. l i v e
c e l l u l a r o r
v i r a l
( k i l l e d )
s u b c e l l u l a r
o r s u b v i r a l
f r a c t i o n s
( s u b u n i t )
c o r p u s c u l a r
( p a r t i c u l a t e )
p r o d u c e d b y
b i o s y n t h e s i s :
( t o x o i d s )
p r o d u c e d b y
p e p t i d e s y n t h e s i s
( s y n t h e t i c
p e p t i d e s )
p r o d u c e d b y
g e n e c l o n i n g
( r e c o m b i n a n t
v a c c i n e v e c t o r s )
m o l e c u l a r
n o n - l i v e
( i n a c t i v a t e d )
v a c c i n e s
TYPES of VACCINES (see the Manual!)

21. CLASSIFICATION of VACCINES
by the NATURE of ANTIGEN
•Live vaccines: contain alive but weakened
microbes that are less virulent to human
divergent vaccines (e.g., smallpox vaccine)
(comes from “divergency” - a moving or spreading apart or in
different directions; the condition of being unlike or
dissimilar)
attenuated (e.g., BCG vaccine)
selective (e.g., oral Sabin poliomyelitis
vaccine)
recombinant (e.g., live influenza vaccine)

22. CLASSIFICATION of VACCINES
by the NATURE of ANTIGEN
•Non-live vaccines (inactivated) : contain
killed microbes of virulent strains, their
derivatives or products
killed (e.g., Salk poliomyelitis vaccine)
subunit (e.g., Hib vaccine)
split (e.g., Influenza vaccine)
molecular (e.g., toxoids, DT-vaccine)
recombinant (e.g., hepatitis B vaccine)

23. CLASSIFICATION of VACCINES
by the QUANTITY of ANTIGENS
•Monovalent vaccines (e.g., BCG)
•Polyvalent or associated vaccines (e.g.,
pentatoxoid, etc.)
•Combined vaccines (e.g., combined
cholera vaccine)

24. LIVE VACCINES
•contain living microbes
•permit replication of the microbe in the host,
increasing antigenic stimulation
•cause vaccine-induced mild infection mimicking
the early stages of natural infection

25. LIVE VACCINES
Advantages: They
•induce prolonged immunity
•usually do not require booster vaccination
•are usually administered via ‘natural way’
(non-invasive procedure)
•stimulate local (mucosal) and systemic
immunity
(NOTE: if given locally, e.g., per os, per nose)
•can be shed in a population
(NOTE: i.e., they induce “immunity in a community”)

26. LIVE VACCINES
Disadvantages: They have safety problems due to:
•insufficient attenuation;
•risk of reversion to wild strain;
•possible contamination by living microbes or toxins;
•high risk of vaccine-associated infection;
•low stability;
•requirements of the “cold chain” between the
factory and the clinic
NB: Live vaccines cannot be
administered to
immunocompromised persons!!!

27. LIVE VACCINES: methods of attenuation
–Serial passages in cells cultured in vitro
–Serial passage in nutrient culture media under
unfavorable conditions
–Adaptation to low temperatures
–Selection of spontaneous mutants
–Chemical mutagenesis

28. The Oral Polio Vaccine
•Live attenuated vaccine was originally produced by allowing
viruses to grow in unusual conditions and selecting the
randomly occurring mutants that had lost virulence

29. KILLED VACCINES
•contain microbes that have been inactivated by
chemical or physical means
•also termed a ’particulate’ or ‘corpuscular’
vaccines, because contain a whole particle of a
pathogen

30. KILLED VACCINES: methods of vaccine
strains inactivation
Chemical methods (formaldehyde, phenol,
acetone, beta-propiolactone)
Physical methods (simple heating, ultraviolet light),
etc.

31. KILLED VACCINES
Advantages: they
•are safe
•cannot reverse to a wild strain
•sterile
•stable during storage
•can be given to immunocompromised
people
•are easily produced
•rather cheap

32. KILLED VACCINES
Disadvantages:
Low immunogenic
Require booster injections
Require using of adjuvants
Cannot induce local immunity
Potential safety problems include:
Contamination by live microbes or toxins
Allergic or autoimmune reactions
Incomplete killing of a pathogen

33. SUBUNIT and SPLIT VACCINES
•contain purified protective antigens of microbes
isolated by chemical means or by splitting a viral
particle

34. SUBUNIT and SPLIT VACCINES
Advantages: cannot cause allergic or autoimmune
reactions
•safe
•cannot reverse to a wild strain
•sterile
•stable during storage
•can be given to immunocompromised people
•of low cost
•polyvalent or combined vaccines can be prepared to
shorten the number of injections

35. SUBUNIT and SPLIT VACCINES
Disadvantages:
Low immunogenic
Contain T-cell-independent antigens
Fail to stimulate T-cells, that is: induce only
primary response
Ineffective in children under 2 years
Require using of adjuvants

36. Adjuvants
•Adjuvant (Latin, adjuvans=“helper”)
•Adjuvant is a substance that enhances the
immune response when injected along with
the antigen
•e.g., Aluminum hydroxide gel, Aluminum phosphate,
Calcium phosphate, etc.
•Antigen adsorbed onto the adjuvant is released slowly,
increasing and promoting antibody formation
•Is used as immunomodifier, stimulating immune
response non-specifically
•The adsorbed antigen exhibits minimal toxicity

37. Effect of Adjuvants
•Antibody response of
mice to egg albumin
•Blue symbols – egg
albumin in saline
•Red symbols – egg
albumin in Freund’s
incomplete adjuvant

38. MOLECULAR VACCINES
•Contain soluble antigens
•Induce strong immunity
•Toxoids induce antitoxic immunity

39. MOLECULAR VACCINES: toxoids
•Toxoid is the molecular vaccine containing
inactivated form of bacterial exotoxin that
is antigenically identical to the active
toxin, but is not toxic

40. MOLECULAR VACCINES: toxoids
•Are prepared by the following way (Ramon method):
 0.4 % formaldehyde
during 4 weeks
 at 40
o
C

41. MOLECULAR VACCINES: toxoids
Advantages:
•Highly immunogenic
•Safe
•Sterile
Disadvantages:
•Possible contamination by toxins
•Call for adjuvant
•May occasionally cause allergic reaction or
infiltration at the injection site

42. Live versus non-live vaccines
Live Non-live
Preparation attenuation inactivation
Administration may be natural route;
may be single dose
injection;
multiple doses
Adjuvant not required usually required
Safety may revert to virulencerequires safe method of
inactivation
Heat lability requires ‘cold chain’ satisfactory
Cost high low
Duration of
immunity
usually years may be long or short
Immune
response
IgG, IgA and
cell-mediated
mainly IgG,
little or no cell-mediated

43. The Modern Vaccines: new approaches
•Recombinant and vector vaccines
•Synthetic peptides
•DNA vaccines
•Edible vaccines

44. Recombinant (vector) vaccines
•“Vector” is an organism that is
modified to include genes
from another source
•The genes coding for antigens
are inserted into a large virus,
e.g., cowpox (vaccinia) virus
•The viruses with recombinant
genome replicate and release
antigens into the host
•Another name – “piggyback
vaccine”

45. Recombinant (vector) vaccines
Advantages:
Stable
Cheap
Easy to make
Produce long-lasting protection
Stimulate both humoral and cell-mediated immunity
Disadvantages:
Continuous antigenic stimulus may lead to tolerance
or autoimmunity
Picture: Electron micrograph of purified 22 nm hepatitis B surface antigens expressed
in yeast cells

46. Synthetic peptides
•Contain chemically synthesized the amino
acid sequences of purified protein antigens
•Vaccines have been created using peptides of
HBs antigen of hepatitis В virus, S. pyogenes M
protein, diphtheria toxin, Influenza virus, etc.
•They do not contain contaminating materials
that might harm the host

47. Synthetic peptides
The problems:
Genetic non-responsiveness of some vaccine
recipients
Must contain T- and B-cells epitopes
Low immunogenic
Require a ‘carrier molecule’
Require high technology

48. DNA vaccines
•Contain purified microbial DNA with a
suitable promoter
• Promote cell-mediated immunity
•To induce immunologic memory require
booster with the protein
•Require high technology
•Are not employed currently for routine human
or veterinary use
•DNA vaccines against influenza are now
tested on animals

49. Edible vaccines
•Is the novel approach to vaccination
•Edible plant tissues are employed
•The transgenic plants - potatoes, tomatoes,
banana, and tobacco plants can be used
•It is cheap way of vaccination
•The promising results of animal experiments
(in mice) have been obtained

50. The components of vaccines
•Antigenic material (protective antigens)
•Stabilizer
•Preserving agent
•Adjuvant

51. Indications for Vaccination
Childhood immunization
Vaccination of risk groups
Immunization of occupational risk
groups
Immunization in endemic areas
Post-exposure protection
Treatment of chronic disease

52. Vaccines Used for Treatment
•Non-live inactivated (killed) vaccines
•Induce escaping intracellular parasites from cells
•Microbes outside the cell are easily engulfed by
phagocytes and come to a contact with antibodies
•Using of vaccines leads to recovery
•Are employed for treatment of chronic cases of:
Gonorrhea
Herpes simplex infections
Staphylococcal infections
Brucellosis, etc.

53. The ‘anti-vaxxers’ concern:
Possible Risk of Complications of Vaccination
vaccine complication
live measles, mumps
killed measles, RSV
Hypersensitivity
to egg antigens
to viral antigens
pertussis, measles
(1 per 100 million doses)
Convulsions, encephalitis
mumps (1 per million doses)Meningitis
rubella Arthritis
MMR Autism ???
HPV DEATH???

54. ‘Giving kids vaccines is the absolute, unambiguous standard of care’
‘You think you are protecting children
through extracts and homeopathy and
positive thoughts and Laws of
Attraction and dancing by candlelight
on a full moon? YOU AREN’T!’

55. PASSIVE IMMUNIZATION

56. Passive Immunization
•Is by injection of preformed antibodies of
known specificity that:
are obtained from human (homologous) or
animal (heterologous) source
(heterologous antibodies are produced
by hyperimmunization of horses or cows)
induce antitoxic, antibacterial or antiviral immunity
produce short-term protection
are used for post-exposure prophylaxis and
treatment of infectious diseases (=immunotherapy)
can be a life-saving treatment

57. a n t i t o x i n s
a n t i s e r a
a n t i t o x i c
" n o r m a l "
n o n - s p e c i f i c
p o o l e d
h u m a n s e r u m
s p e c i f i c
i m m u n o g l o b u l i n s
a n t i m i c r o b i a l
i m m u n o g l o b u l i n s m o n o c l o n a l
a n t i b o d i e s
A n t i b o d y -
c o n t a i n i n g
p r e p a r a t i o n s
see the Manual:

58. Indications for Passive Immunization
infection source of
antibody
indication
Diphtheria Human, horseProphylaxis, treatment
Tetanus
Varicella zosterHuman Prophylaxis in
immunodeficiencies
Gas gangrene Horse Post-exposure prophylaxis
and treatment
Botulism
LeptospirosisBuffalo, ox Treatment
Rabies Human Post-exposure (+vaccine)
Hepatitis B Human Post-exposure
Hepatitis A Pooled human
immunoglobulin
Prophylaxis (travel)
Measles Post-exposure prophylaxis

59. IMMUNOMODIFIERS
(syn.: IMMUNOMODULATORS )
•Is a group of immune biological
preparations, endogenous or exogenous,
that can specifically or non-specifically
effect human immune system
•Can either stimulate immune response
(“immunostimulators”) or
•suppress the immune system –
“immunosuppressants”
(syn.: “immunodepressants”)

60. IMMUNOMODIFIERS
Endogenous immunostimulators:
Interferons
Interleukins
Thymus peptides
Myelopeptides
TNF
Chemokines
Exogenous immunostimulators:
Biological and chemical derivatives of bacterial,
animal, or plant source
Adjuvants
Vitamins A, B or C, etc.

61. IMMUNOMODIFIERS
Immunosuppressants:
•Glucocorticoids
•Cyclosporine A
•Anti-proliferative and Anti-Metabolic Drugs, etc.

62. ADAPTOGENES
•Is a group of preparations that can
non-specifically effect host
metabolism
•Stimulate metabolic processes
•Regulate nervous system function
•Regulate hormone balance
•Are capable to activate immune system
•May possess antimutagenic activity
•Are made of plants (e.g., ginseng)

63. Lecture Quiz
1.What infectious disease was completely
eradicated in the world due to effective
vaccination?
2.Who gave the name to vaccines?

64. That is all for now!

65. Good luck on the colloquium!
Happy Holidays!!!

66. TOXOIDS

67. Recombinant (vector) vaccines

68. Vaccine Adjuvants
Inorganic salts
aluminum hydroxide (alhydrogel)*
aluminum phosphate*
calcium phosphate*
beryllium hydroxide
Delivery systems
liposomes**
immune-stimulating complexes (ISCOMs)**
slow release formulations**
non-ionic block co-polymeres
Bacterial products
BCG
killed mycobacteria (complete Freund’s adjuvant)
†
muramyl dipeptide (MDP)
†
toxoids*
Natural mediators**
IL-1
IL-2
IFNγ
IL-12
* - routinely used in man
** - experimental
†
- too toxic for man use

69. Recombinant (vector) vaccines
•A variety of viruses, bacteria and eukaryotes (yeasts) can
be used for cloned genes
•Picture: A principle of inserting genes into the vaccinia
virus Ankara

70. Complications of Vaccination
•The number of
whooping cough
cases after the
introduction of mass
immunization (1958)
•Following the scare
about the possible
adverse effects of
pertussis vaccine, the
number of cases rose
(1978-1979)

71. The Effect of Vaccination on the Incidence of
Viral Diseases in USA
•The dramatic downward trend after the introduction of a vaccines

72. Global deaths from
eight vaccine-preventable diseases
Infectious disease Annual deaths
(estimated)
Poliomyelitis
Diphtheria
Pertussis
Measles
Tetanus
Haemophilus influenzae B
Hepatitis B
Yellow fever
720
5 000
346 000
888 000
410 000
400 000
900 000
30 000

73. There are no satisfactory vaccines against:
organism disease
HIV
Hepatitis C virus
Herpes simplex virus
Cytomegalovirus
Epstein-Barr virus
Rhinoviruses
Dengue virus
AIDS
Hepatitis C
Genital herpes
Effect on fetus
Glandular fever
Common cold
Dengue fever
N. gonorrhoeae
M. tuberculosis
M. leprae
T. pallidum
C. trachomatis
Gonorrhea
Tuberculosis
Leprosy
Syphilis
Trachoma, urethritis
Plasmodium spp.
Trypanosoma spp.
Malaria
Trypanosomiasis

74. Passive Immunization
•significantly reduced
the incidence of tetanus
in the early months of
the 1
st
World War
•The figure shows the
incidence of tetanus per
1000 wounded soldiers
in British hospitals
during 1914-1916

75. Non-specific Cellular Immunostimulation
Microbial Coley’s toxin (filtered cultures of
Streptococci and Serratia marcescens)
BCG
Muramyl dipeptide
Prodigiosan
Pyrogenal, etc.
Endogenous Cytokines
Thymus factors (“Thymalin”, “Tactivin”)
TNF
CSF
Myelopeptides
Hormones
?Transfer factor, etc.

76. Possible Side Effects of Cytokine Therapy
Interferons Fever
Malaise
Fatigue
Muscle pains
Toxicity to kidney, liver, heart,
bone marrow
IL-2 Vascular leak syndrome that includes:
hypotension
pulmonary edema
renal failure
hepatic failure
Mental changes
Coma
TNF-α Shock

77. KILLED VACCINES
•Methods for vaccine strains inactivation
organismorganism method of inactivationmethod of inactivation
VirusesViruses::
RabiesRabies
InfluenzaInfluenza
Poliomyelitis (Salk strain)Poliomyelitis (Salk strain)
Hepatitis AHepatitis A
ß-propiolactoneß-propiolactone
formaldehydeformaldehyde
Bacteria:Bacteria:
S.typhiS.typhi
V.choleraeV.cholerae
B.pertussisB.pertussis
Y.pestisY.pestis
heat+phenol or acetoneheat+phenol or acetone
heatheat
heat or formaldehydeheat or formaldehyde
formaldehydeformaldehyde

78. Indications for Pooled Normal Human
Immunoglobulin Therapy
•The post-exposure prophylaxis of
infectious diseases
•Prevention of recurrent infections in
patients with hypogammaglobulinemia
•Common variable deficiency correction
•Chronic lymphocytic leukemia
•Post-bone marrow transplantation
•?AIDS