By Prof.Dr.Abdelhady Mesbah

1. Use of Vaccines
&
Immunoglobulins in Persons with
Altered Immunocompetence
By : Dr.Abdelhady Mesbah M.D.
Fellow Of The American Academy Of
Immunology

29. Severe immunosuppression
Can be due to a variety of conditions:
• Congenital immunodeficiency.
• Human Immunodeficiency Virus infection.
• Malnutrition
• Leukemia.
• Lymphoma.
• Generalized malignancy.
• Therapy with Alkylating agents.
• Antimetabolites.
• Radiation.
• Large amounts of Corticosteroids

30. thro u g h a nu mb e r o f
m e c h a n is m s : It w e a k e n s
e p it h e lia l in t e g r it y , m a y
h a ve a p ro fo u nd e ffe c t o n
c e l l -m e d i a t e d i m m u n i t y ,
w it h f u n c t io n a l d e f ic ie n c ie s
in im m u n o g lo b u lin s a n d
d e f e c t s in p h a g o c y t o s is .
M a ln u t r it io n a ls o m a y
in it ia t e a " v ic io u s c y c le " o f
in f e c t io n p r e d is p o s in g t o
m a ln u t r it io n a n d g r o w t h
f a lt e r in g , w h ic h in t u r n m a y
le a d t o a n in c r e a s e d r is k
f o r f u r t h e r in f e c t io n .

31. As for diarrhea, in studies in Bangladesh,
malnourished and well-nourished
children had the same number of
infections with diarrheal pathogens such
as entero-toxigenic E . coli;. However,
diarrhea in malnourished children was of
longer duration and had greater potential
long-term nutritional consequences (42).
Overall, malnutrition appears to result in
a 30-fold increase in the risk -associated
death

32. While accurate data on the prevalence of
malnutrition are difficult to obtain,
problems are accentuated in developing
countries, in areas of political unrest, and
among marginalized populations in the
United States and other affluent nations.
In Mexico, according to a probabilistic
survey in 1990, 42.3% of children under
5 years of age had some degree of
malnutrition (40).

33. • Immunocompromised patients :
• For some of these conditions, all affected persons
will be severely immunocompromised.
• For others, such as HIV infection, the spectrum of
disease severity due to disease or treatment stage
will determining the degree to which the immune
system is compromised.
• The responsibility for determining whether a patient
is severely immunocompromised ultimately lies
with the physicians.

34. Killed or Inactivated Vaccines
• These vaccines do not represent a danger to
immunocompromised persons.
• Generally should be administered as recommended
for healthy persons.
• Frequently, the immune response of
immunocompromised persons to these vaccine
antigens is not as good as that of immunocompetent
persons; higher doses or more frequent boosters may
be required, although even with these modifications, the
immune response may be suboptimal.

35. Killed or inactivated vaccines do not
represent a danger to immunocompromised
persons and should be administered as
recommended for healthy persons. In,
contrast live-virus vaccines and live-bacteria
vaccines such as M ycobacterium bovis BCG are
contraindicated for persons that are severely
immunocompromised. Oral polio vaccine is
contraindicated to any person that is in contact
(health care providers and household
contacts) with a severely immunodepressed
patient

36. Steroid Therapy
• Short term therapy (less than 2 weeks); low to
moderate dose; long-term, alternate-day treatment
with short-acting preparations; maintenance
physiologic doses (replacement therapy);
administered topically ,(skin or eyes), by aerosol, or
by intra-articular, bursal, or tendon injection,usually
does not contraindicate administration of live - virus
vaccine.

37. • The immunosuppressive effects of steroids
treatment vary, but many clinicians consider a dose
Of Hydrocortisone equivalent to either 2mg/kg of
body weight or a total of 20mg/day of prednisone
as sufficiently immunosuppressive to raise concern
about the safety of immunization with live-virus
vaccines.
• Corticosteroids used in greater than physiologic
doses also may reduce the immune response to
vaccines.

38. • Physicians should wait at 3 least
months after discontinuation of therapy
before administering a live-virus vaccine
to patients who have received high-
doses, systemic steroids for greater
than or equal 2 weeks.

39. • For specific immunocompromising conditions
“ e.g. asplenia”, such patients may be at higher risk
for certain diseases, and additional vaccines,
particularly bacterial polysaccharide vaccines are
recommended for them “ e.g. Haemophilus
influenzae type b, pneumococcal and meningoccal”

40. Specific Immunocompromising
Conditions
Persons with immunocompromising conditions may
be divided into 3 groups:
• Persons who are severely immunocompromised
not as a result of HIV infection.
• Persons with HIV infection.
• Persons with conditions that cause limited immune
deficits (e.g. asplenia, renal failure) that may
require use of special vaccines or higher doses of
vaccines but that do not contraindicate use of any
particular vaccine.

41. Patients with limited immuno-
compromising conditions (e.g.,
Malnutrition , asplenia, diabetes,
alcoholic cirrhosis) may be at higher
risk for certain diseases, and
additional vaccines, particularly
bacterial polysaccharide vaccines
(Ha e mo p h il u s in f l u e n z a type
b - Hib, pneumococcal and
meningococcal), are recommended for
them.

42. Prevention and Treatment of
Virus Diseases: Vaccines
•There are two aspects to the
prevention and treatment of virus
diseases:
•Prevention: Vaccination and public
health measures
•Treatment: Antivirals

43. Post Exposure Vaccination
• Although prevention of infection is much
the preferred option, post-exposure
vaccines can be of great value in
modifying the course of some virus
infections e.g. rabies.
• To design effective vaccines, we need to
understand immune response to virus
infection.

44. Cell Mediated Immunity: T cells:
• Cell mediated immunity is particularly important
in virus infections. Healthy Th Cells is Crucial For
both cellular and humoral response.
CD8 cells, Cytotoxic T ymphocytes or CTL cells.
Agammaglobulinaemic children are not especially
at risk of viral infections such as measles. In
contrast if they lack T cells then measles is fatal.
T cells are able to recognise virus infected cells
early in the infection process.

45. • MHC Class I is present on all nucleated cells with
the exception of neurons. They present
endogenous (intracellular) antigens including viral
ones i.e before virus is released from a cell. T cell
receptor can recognise antigen-MHC I complexes.
MHC Class I is present on antigen presenting cells
such as macrophages T and B cells. These cells
take up exogenous (extracellular) antigens ie they
can only present viral antigens from another cell,
after replication and release.

46. MHC I is more important in clearing
viral infections. If the MHC I system is
knocked out then people can still clear
virus infections but less quickly.
Presumably viral replication occurs and
exogenous viral proteins are processed
by MHCII cells.

47. Vaccination Strategies
• There are three basic types of vaccines:
– 1) Sub-unit Vaccines
• The newest type; completely safe, except for
rare adverse reactions. Unfortunately, they
also tend to be the least effective.
• Problems: (Relatively) poor antigenicity
(especially short peptides)
• Vaccine delivery (carriers/adjuvants needed)

48. 1) Sub-unit Vaccines
a) Synthetic Vaccines :
Not very effective, Great
potential,None currently in use.
b) Recombinant Vaccines :
Better than above - some
success has already been
achieved:
HBV - now produced in yeast.

49. 1) Sub-unit Vaccines
c) Virus Vectors
The idea is to utilize a well-
understood, attenuated virus to
present antigens to immune system,
e.g: Vaccinia Virus ,Attenuated
polioviruses ,Retroviruses (gene
therapy)
Hard to produce, safe?, none
successful yet - lots of trials
underway.

50. 2) Inactivated Vaccines
• Method of production : exposure to
denaturing agent - results in loss of
infectivity without loss of antigenicity.
• Advantages:
• More effective than Subunit Vaccine,
better immunogens, Stable.
• Little or no risk (if properly inactivated)

51. 2) Inactivated Vaccines
Disadvantages:
* Not possible for all viruses;
* denaturation may lead to loss of
antigenicity, e.g. measles.
* Not as effective at preventing infection
as live viruses (mucosal immunity -
IgA).
* May not protect for a long period ?

52. 3) Live Virus Vaccines
•The use of virus with reduced
pathogenicity to provide immune
response without disease. May be
naturally occurring virus (e.g.
Jenner, cowpox, 1776 (Variolation))
or artificially attenuated (oral
poliovirus vaccine (OPV)).

53. Advantages of Live attenuated vaccines:
Good immunogens Induce long-lived,
appropriate immunity
Disadvantages:
Unstable: biochemically (live virus) and
genetically (reversion to virulence)
Not possible to produce in all cases
- trial and error black box !
Contamination possible (SV40)
Inappropriate vaccination e.g.
immunocompromised hosts / rubella in
pregnancy may lead to disease

54. • Administration
• Oral: o
• Subcutaneous or scarification: sc
• Intramuscular: im
• Adjuvants
• These enhance the immune response
and are included in inactivated and
subunit vaccines e.g aluminium
hydroxide. This is considered safe for
human use.

55. Passive immunisation
• Normal pooled human immunoglobulin fraction.
Heat treated to destroy viruses. Considered as safe
e.g.: Prevention of Hepatitis A,Prevention or
modification of measles in the immuno -
compromised who have been in contact with a
case.
HBV Ig is coadministered with the vaccine to
provide rapid protection after say a needlestick
injury. Rabies Ig immediately after exposure.
Varicella Zoster Ig to the immunosuppressed and
leukaemic. Lassa Fever convalescent plasma is
therapeutic.

56. Problems of passive Immunization
Sensitisation, reversion, rare possible
complications. Attenuated vaccines not
given to pregnant or immune
compromised.
Developing effective vaccines to some
viruses is proving very difficult e.g.
influenza, common cold viruses, HIV-1,
herpes, papilloma and more. Common
problems include the existence of many
serotypes, antigenic drift and shift.

57. The Future Of Vaccination ?
 Genetic engineering
 DNA vaccines"
The Emerging Role of DNA Vaccines"
 Synthetic peptides
 Improved adjuvants, liposomes,
ISCOMS (saponin complexes)

58. Hepatitis B vaccination in low and nonresponder patients
Low or nonresponse to hepatitis B vaccination is seen
in only a small proportion of people vaccinated with
an adequate schedule and :
1-May have a genetic basis .
2-Nonresponders have a lower cytokine response to
the vaccine than responders .
3-The rate of low or nonresponse is much higher in
patients with uremia , up to 30 % failing to respond
to the usual vaccination schedules.
4-Coinfection with hepatitis C seems to further lower
the response rate in such patients . In a recent study,
hepatitis C was identified as a reason for non-
response (31 % vs 9 % in healthy health staff).

59. High dose boosting induced a response in 80 %,
however the federal office of health recommends
repeated i.m. booster injections for such patients.
If this does not achieve the goal, it states that repeated
reinjections at short intervals may be considered but
considers such a procedure to be controversial.

60. Revaccination with regular i.m. Injections
may be appropriate for immunocompetent
subjects, in particular health care
workers. Thus, in a post-marketing
surveillance , all complying
Nonresponders achieved satisfactory anti-
HBs levels after receiving bimonthly 20 µg
i.m. until a satisfactory response had been
achieved . This holds also true for children
not responding to perinatal vaccination.

61. The situation is different in immuno -compromised
subjects, in particular in-patients with renal
insufficiency.
Low- or nonresponse in renal failure patients as a
function of age and increased serum creatinine .
Lack of vaccination leads frequently to significant
morbidity and forcing a protective effects is therefore
highly desirable.

62. Different approaches have been selected to
achieve satisfactory protection in such
patients, in particular the use of repeated
intradermal injections and the addition of
cytokines to the vaccination. Doubling the
dose in renal insufficiency should probably
be used in the first time vaccination
already. Finally, newer recombinant
vaccines containing preS1 and
preS2 components may be more efficient
but direct comparisons are yet lacking.

63. Intradermal versus intramuscular application
Different open studies in the early 90's have
suggested that intradermal injections could enhance
the response to vaccination . In immunocompetent
patients this has been suggested . Different
controlled trials, have backed up this contention.
Unfortunately, different doses and injection
schedules have been used rendering a formal meta-
analysis impossible. The study of Fabrizi and
colleagues compared revaccination with equal dose
intradermal administration and found the latter to
be clearly superior .

64. Table
Compilation of randomized trials (RCT)
and open studies investigating intradermal
administration of hepatitis B vaccine. RR
stands for response rate, duration - if stated
- for the duration protective levels of anti-
HBs had been observed.

65. Type of N Dose id RR Duration
study
RCT 81 20 µg x 5 100 % 70 % at 3
y
RCT 50 80 µg total 100 vs 48 57 % at 1
% y
RCT 30 5 µg x 12 93 vs 73 not given
%
Open 12 5 µg x 4 - 100 % not given
8
Open 31 10 µg x 4 61 vs 64 not given
%
Open 20 5 µg up to 70 % not given
70 µg
Open 19 5 µg 94 % not given
Open 5 5 µg x 3 - 100 % not given
7
Open 9 20 mg x 3 89 % not given

66. Triple antigen vaccine:
The novel vaccines with triple antigen will
enter the market soon; 79 % of healthcare
workes previously not responding
sufficiently to the old vaccine responded
with protective anti-HBs titers .

67. Conclusions
•As low- or nonresponse as a function of
age and serum creatinine, vaccination
should be performed as early as possible
in the course of the disease in patients
with renal failure .
•The new triple antigen vaccines are
anticipated to be more potent . Studies
are eagerly awaited and are being
published
•Double dose should be used in-patients
with chronic renal failure .

68. • The largest randomized controlled trial
suggest that 5 intradermal doses of 20 µ g
can achieve protective levels of anti-HBs in
all patients persisting for 3 years in 70 %
of them . It can be recommended to use
either 5 consecutive 20 µ g doses as in the
study quoted above; alternatively,
vaccination can be carried out until a
satisfactory anti-HBs level has been
achieved.
Patients failing an intradermal regime can be
considered for adjuvant cytokine treatment or
for vaccination with newer vaccines with
better immunogenic properties.

69. CLASSIFICATION OF IMMUNODEFICIENCY DISEASES:
PRIMARY IMMUNODEFICIENCIES:
X-linked agammaglobulinaemia
hypogammaglobulinaemia of infancy
Immune deficiencies IgA deficiency
affecting B cell function: IgG subclass deficiency, and selective antibody
deficiency with normal immunoglobulins
common variable immune deficiency
Combined T and B cell
severe combined immunodeficiency
deficiencies:
"Pure" T cell mucocutaneous Candidiasis
immunodeficiencies: X-linked lymphoproliferative syndrome
Primary syndromes which di George anomaly
are associated with Wiskott-Aldridge syndrome
immunodeficiency: ataxia telangiectasia
Primary defects of chronic granulomatous disease
phagocytic function: leukocyte adhesion deficiency
C1 inhibitor deficiency (hereditary
angioedema)
Complement deficiencies:
Deficiencies of individual complement
components

70. C L A S S IF IC A T IO N O F
IM M U N O D E F IC IE N C Y D IS E A S E S :
infections (e.g. HIV)
lymphoproliferative diseases (e.g.
CLL, multiple myeloma)
SECONDARY causes of reduced production of
MMUNODEFICIE immune components, e.g.
NCIES: malnutrition, drugs
loss or increased catabolism of
immune components e.g. protein
losing enteropathy, nephrotic
syndrome, burns