Use of Vaccines & Immunoglobulins in Persons with Altered Immunocompetence By : Dr.Abdelhady Mesbah M.D.Fellow Of The American Academy Of Immunology
Severe immunosuppressionCan 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
thro u g h a nu mb e r o fm e c h a n is m s : It w e a k e n se p it h e lia l in t e g r it y , m a yh a ve a p ro fo u nd e ffe c t o nc 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 sin im m u n o g lo b u lin s a n dd 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 yin it ia t e a " v ic io u s c y c le " o fin f e c t io n p r e d is p o s in g t om a ln u t r it io n a n d g r o w t hf a lt e r in g , w h ic h in t u r n m a yle a d t o a n in c r e a s e d r is kf o r f u r t h e r in f e c t io n .
As for diarrhea, in studies in Bangladesh,malnourished and well-nourishedchildren had the same number ofinfections with diarrheal pathogens suchas entero-toxigenic E . coli;. However,diarrhea in malnourished children was oflonger duration and had greater potentiallong-term nutritional consequences (42).Overall, malnutrition appears to result ina 30-fold increase in the risk -associateddeath
While accurate data on the prevalence ofmalnutrition are difficult to obtain,problems are accentuated in developingcountries, in areas of political unrest, andamong marginalized populations in theUnited States and other affluent nations.In Mexico, according to a probabilisticsurvey in 1990, 42.3% of children under5 years of age had some degree ofmalnutrition (40).
• 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.
Killed or Inactivated Vaccines• These vaccines do not represent a danger toimmunocompromised persons.• Generally should be administered as recommendedfor healthy persons.• Frequently, the immune response ofimmunocompromised persons to these vaccineantigens is not as good as that of immunocompetentpersons; higher doses or more frequent boosters maybe required, although even with these modifications, theimmune response may be suboptimal.
Killed or inactivated vaccines do notrepresent a danger to immunocompromisedpersons and should be administered asrecommended for healthy persons. In,contrast live-virus vaccines and live-bacteriavaccines such as M ycobacterium bovis BCG arecontraindicated for persons that are severelyimmunocompromised. Oral polio vaccine iscontraindicated to any person that is in contact(health care providers and householdcontacts) with a severely immunodepressedpatient
Steroid Therapy• Short term therapy (less than 2 weeks); low tomoderate dose; long-term, alternate-day treatmentwith short-acting preparations; maintenancephysiologic doses (replacement therapy);administered topically ,(skin or eyes), by aerosol, orby intra-articular, bursal, or tendon injection,usuallydoes not contraindicate administration of live - virusvaccine.
• The immunosuppressive effects of steroidstreatment 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 physiologicdoses also may reduce the immune response tovaccines.
• 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.
• For specific immunocompromising conditions“ e.g. asplenia”, such patients may be at higher riskfor certain diseases, and additional vaccines,particularly bacterial polysaccharide vaccines arerecommended for them “ e.g. Haemophilusinfluenzae type b, pneumococcal and meningoccal”
Specific Immunocompromising ConditionsPersons 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.
Patients with limited immuno-compromising conditions (e.g.,Malnutrition , asplenia, diabetes,alcoholic cirrhosis) may be at higherrisk for certain diseases, andadditional vaccines, particularlybacterial polysaccharide vaccines(Ha e mo p h il u s in f l u e n z a typeb - Hib, pneumococcal andmeningococcal), are recommended forthem.
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
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.
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.
• 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.
MHC I is more important in clearingviral infections. If the MHC I system isknocked out then people can still clearvirus infections but less quickly.Presumably viral replication occurs andexogenous viral proteins are processedby MHCII cells.
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)
1) Sub-unit Vaccinesa) Synthetic Vaccines :Not very effective, Greatpotential,None currently in use.b) Recombinant Vaccines :Better than above - somesuccess has already beenachieved:HBV - now produced in yeast.
1) Sub-unit Vaccinesc) Virus VectorsThe idea is to utilize a well-understood, attenuated virus topresent antigens to immune system,e.g: Vaccinia Virus ,Attenuatedpolioviruses ,Retroviruses (genetherapy)Hard to produce, safe?, nonesuccessful yet - lots of trialsunderway.
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)
2) Inactivated VaccinesDisadvantages:* Not possible for all viruses;* denaturation may lead to loss ofantigenicity, e.g. measles.* Not as effective at preventing infection as live viruses (mucosal immunity -IgA).* May not protect for a long period ?
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)).
Advantages of Live attenuated vaccines:Good immunogens Induce long-lived,appropriate immunityDisadvantages:Unstable: biochemically (live virus) andgenetically (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 inpregnancy may lead to disease
• 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.
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.
Problems of passive ImmunizationSensitisation, reversion, rare possiblecomplications. Attenuated vaccines notgiven to pregnant or immunecompromised.Developing effective vaccines to someviruses is proving very difficult e.g.influenza, common cold viruses, HIV-1,herpes, papilloma and more. Commonproblems include the existence of manyserotypes, antigenic drift and shift.
The Future Of Vaccination ? Genetic engineering DNA vaccines" The Emerging Role of DNA Vaccines" Synthetic peptides Improved adjuvants, liposomes, ISCOMS (saponin complexes)
Hepatitis B vaccination in low and nonresponder patientsLow or nonresponse to hepatitis B vaccination is seenin only a small proportion of people vaccinated withan adequate schedule and :1-May have a genetic basis .2-Nonresponders have a lower cytokine response tothe vaccine than responders .3-The rate of low or nonresponse is much higher inpatients with uremia , up to 30 % failing to respondto the usual vaccination schedules.4-Coinfection with hepatitis C seems to further lowerthe 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).
High dose boosting induced a response in 80 %,however the federal office of health recommendsrepeated i.m. booster injections for such patients.If this does not achieve the goal, it states that repeatedreinjections at short intervals may be considered butconsiders such a procedure to be controversial.
Revaccination with regular i.m. Injectionsmay be appropriate for immunocompetentsubjects, in particular health careworkers. Thus, in a post-marketingsurveillance , all complyingNonresponders achieved satisfactory anti-HBs levels after receiving bimonthly 20 µgi.m. until a satisfactory response had beenachieved . This holds also true for childrennot responding to perinatal vaccination.
The situation is different in immuno -compromised subjects, in particular in-patients with renalinsufficiency. Low- or nonresponse in renal failure patients as afunction of age and increased serum creatinine .Lack of vaccination leads frequently to significantmorbidity and forcing a protective effects is thereforehighly desirable.
Different approaches have been selected toachieve satisfactory protection in suchpatients, in particular the use of repeatedintradermal injections and the addition ofcytokines to the vaccination. Doubling thedose in renal insufficiency should probablybe used in the first time vaccinationalready. Finally, newer recombinantvaccines containing preS1 and preS2 components may be more efficientbut direct comparisons are yet lacking.
Intradermal versus intramuscular applicationDifferent open studies in the early 90s havesuggested that intradermal injections could enhancethe response to vaccination . In immunocompetentpatients this has been suggested . Differentcontrolled trials, have backed up this contention.Unfortunately, different doses and injectionschedules have been used rendering a formal meta-analysis impossible. The study of Fabrizi andcolleagues compared revaccination with equal doseintradermal administration and found the latter tobe clearly superior .
Table Compilation of randomized trials (RCT) and open studies investigating intradermal administration of hepatitis B vaccine. RRstands for response rate, duration - if stated - for the duration protective levels of anti- HBs had been observed.
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
Triple antigen vaccine:The novel vaccines with triple antigen willenter the market soon; 79 % of healthcareworkes previously not respondingsufficiently to the old vaccine respondedwith protective anti-HBs titers .
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 .
• 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 beconsidered for adjuvant cytokine treatment orfor vaccination with newer vaccines withbetter immunogenic properties.
CLASSIFICATION OF IMMUNODEFICIENCY DISEASES: PRIMARY IMMUNODEFICIENCIES: X-linked agammaglobulinaemia hypogammaglobulinaemia of infancy Immune deficiencies IgA deficiencyaffecting 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 syndromePrimary 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
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 ofMMUNODEFICIE immune components, e.g. NCIES: malnutrition, drugs loss or increased catabolism of immune components e.g. protein losing enteropathy, nephrotic syndrome, burns