1. Different Types of Vaccine

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Different Types of Vaccine

Whole virus vaccines. either live or killed, constitute the vast majority of vaccines in use at

present. However, recent advances in molecular biology had provided alternative methodsfor producing vaccines. Listed below are the possibilities;-

. Live whole virus vaccines

!. "illed whole virus vaccines

#. $ubunit vaccines;- purified or recombinant viral antigen

%. &ecombinant virus vaccines

'. (nti-idiotype antibodies

). *+( vaccines

1. Live Vaccines

Live virus vaccines are prepared from attenuated strains that are almost or completely

devoid of pathogenicity but are capable of inducing a protective immune response. hey

multiply in the human host and provide continuous antigenic stimulation over a period oftime, rimary vaccine failures are uncommon and are usually the result of inadeuate

storage or administration. (nother possibility is interference by related viruses as is

suspected in the case of oral polio vaccine in developing countries. $everal methods have been used to attenuate viruses for vaccine production.

Use of a related virus from another animal - the earliest e/ample was the use of cowpo/

to prevent smallpo/. he origin of the vaccinia viruses used for production is uncertain.

Administration of pathogenic or partially attenuated virus by an unnatural route - thevirulence of the virus is often reduced when administered by an unnatural route. his

principle is used in the immuni0ation of military recruits against adult respiratory distress

syndrome using enterically coated live adenovirus type %, 1 and 2!3.

Passage of the virus in an "unnatural host" or host cell - the major vaccines used in manand animals have all been derived this way. (fter repeated passages, the virus is

administered to the natural host. he initial passages are made in healthy animals or in

primary cell cultures. here are several e/amples of this approach4 the 1* strain of yellowfever was developed by passage in mice and then in chick embryos. olioviruses were

passaged in monkey kidney cells and measles in chick embryo fibroblasts. Human diploid

cells are now widely used such as the W5-#6 and 7&8-'. he molecular basis for host

range mutation is now beginning to be understood.


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Development of temperature sensitive mutants - this method may be used in conjunction

with the above method.

. !nactivated hole virus vaccines

hese were the easiest preparations to use. he preparation was simply inactivated. heouter virion coat should be left intact but the replicative function should be destroyed. o be

effective, non-replicating virus vaccines must contain much more antigen than live vaccines

that are able to replicate in the host. reparation of killed vaccines may take the route ofheat or chemicals. he chemicals used include formaldehyde or beta- propiolactone. he

traditional agent for inactivation of the virus is formalin. 9/cessive treatment can destroy

immunogenicity whereas insufficient treatment can leave infectious virus capable ofcausing disease. $oon after the introduction of inactivated polio vaccine, there was an

outbreak of paralytic poliomyelitis in the :$( use to the distribution of inadeuately

inactivated polio vaccine. his incident led to a review of the formalin inactivation procedure and other inactivating agents are now available, such as eta-propiolactone.

(nother problem was that $


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Potential safety problems

Live vaccines

. :nderattenuation

!. 7utation leading to reversion to virulence

#. reparation instability

%. 8ontaminating viruses in cultured cells

'. Heat lability

). $hould not be given to immunocompromi0ed or pregnant patients

#illed vaccines

. 5ncomplete inactivation

!. 5ncreased risk of allergic reactions due to large amounts of antigen involved

resent problems with vaccine development include

. >ailure to grow large amounts of organisms in laboratory

!. 8rude antigen preparations often give poor protection. eg. "ey antigen not

identified, ignorance of the nature of the protective or the protective immuneresponse.

#. Live vaccines of certain viruses can 23. induce reactivation, 2!3 be oncogenic innature

$.%&ubunit Vaccines

?riginally, non-replicating vaccines were derived from crude preparations of virus from

animal tissues. (s the technology for growing viruses to high titres in cell culturesadvanced, it became practicable to purify virus and viral antigens. 5t is now possible to

identify the peptide sites encompassing the major antigenic sites of viral antigens, fromwhich highly purified subunit vaccines can be produced. 5ncreasing purification may leadto loss of immunogenicity, and this may necessitate coupling to an immunogenic carrier

protein or adjuvant, such as an aluminum salt. 9/amples of purified subunit vaccines

include the H( vaccines for influen0a ( and , and Hs(g derived from the plasma of

carriers.

'. (ecombinant viral proteins


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urthermore, less uality assurance is reuired. 8hanges due to natural

variation of the virus can be readily accommodated, which would be a great advantage for

unstable viruses such as influen0a.

$ynthetic peptides do not readily stimulate cells. 5t was generally assumed that, becauseof their small si0e, peptides would behave like haptens and would therefore reuire

coupling to a protein carrier which is recogni0ed by -cells. 5t is now known that synthetic

peptides can be highly immunogenic in their free form provided they contain, in addition tothe cell epitope, - cell epitopes recogni0ed by -helper cells. $uch -cell epitopes can be

provided by carrier protein molecules, foreign antigens. or within the synthetic peptide

molecule itself.


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$ynthetic peptides are not applicable to all viruses. his approach did not work in the case

of polioviruses because the important antigenic sites were made up of ! or more differentviral capsid proteins so that it was in a concise #-* conformation.

Advantages of defined viral antigens or peptides include*

. roduction and uality control simpler

!. +o +( or other viral or e/ternal proteins, therefore less to/ic.

#. $afer in cases where viruses are oncogenic or establish a persistent infection

%. >easible even if virus cannot be cultivated

Disadvantages*

. 7ay be less immunogenic than conventional inactivated whole-virus vaccines

!. &euires adjuvant

#. &euires primary course of injections followed by boosters

%. >ails to elicit 875.

+. Anti,idiotype antibodies

he ability of anti-idiotype antibodies to mimic foreign antigens has led to their

development as vaccines to induce immunity against viruses, bacteria and proto0oa ine/perimental animals. (nti-idiotypes have many potential uses as viral vaccines,

particularly when the antigen is difficult to grow or ha0ardous. hey have been used to

induce immunity against a wide range of viruses, including HeL


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5ndeed some observers have already dubbed the new technology the @third revolution@ in

vaccine developmentAon par with asteurBs ground-breaking work with whole organismsand the development of subunit vaccines. he first clinical trials using injections of *+( to

stimulate an immune response against a foreign protein began for H5< in CC'. >our other

clinical trials using *+( vaccines against influen0a, herpes simple/ virus, -cell

lymphoma, and an additional trial for H5< were started in CC).

he techniue that is being tested in humans involves the direct injection of plasmids -

loops of *+( that contain genes for proteins produced by the organism being targeted for

immunity. ?nce injected into the hostBs muscle tissue, the *+( is taken up by host cells,

which then start e/pressing the foreign protein. he protein serves as an antigen thatstimulate an immune responses and protective immunological memory.

9nthusiasm for *+( vaccination in humans is tempered by the fact that delivery of the

*+( to cells is still not optimal, particularly in larger animals. (nother concern is the possibility, which e/ists with all gene therapy, that the vaccineBs *+( will be integrated

into host chromosomes and will turn on oncogenes or turn off tumor suppressor genes.(nother potential downside is that e/tended immunostimulation by the foreign antigen

could in theory provoke chronic inflammation or autoantibody production

Presentation of immunogenic proteins and peptides

roteins separated from virus particles are generally much less immunogenic than the intact

particles. his difference in activity is usually attributed to the change in configuration of a

protein when it is released from the structural reuirements of the virus particle. 7anyattempts have been made to enhance the immunogenic activity of separated proteins.

Ad/uvants

:sed to potentiate the immune response

. >unctions to locali0e and slowly release antigen at or near the site of administration.

!. >unctions to activate (8s to achieve effective antigen processing or presentation

7aterials that have been used include;-

. (luminum salts

!. 7ineral oils

#. 7ycobacterial products, eg. >reudBs adjuvants

!mmunostimulating comple0es !&234&5

. (n alternative vaccine vehicle


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!. he antigen is presented in an accessible, multimeric, physically well defined

comple/

#. 8omposed of adjuvant 2Duil (3 and antigen held in a cage like structure

%. (djuvant is held to the antigen by lipids

'. 8an stimulate 875

). 7ean diameter #'nm

5n the most successful procedure, a mi/ture of the plant glycoside saponin, cholesterol and

phosphatidylcholine provides a vehicle for presentation of several copies of the protein on acage-like structure. $uch a multimeric presentation mimics the natural situation of antigens

on microorganisms. hese immunostimulating comple/es have activities euivalent to

those of the virus particles from which the proteins are derived, thus holding out great

promise for the presentation of genetically engineered proteins.

$imilar considerations apply to the presentation of peptides. 5t has been shown that by

building the peptide into a framework of lysine residues so that 6 copies instead of copy

are present, the immune response induced was of a much greater magnitude. ( novel

approach involves the presentation of the peptide in a polymeric form combined with cellepitopes. he seuence coding for the foot and mouth disease virus peptide was e/pressed

as part of a fusion protein with the gene coding for the Hepatitis core protein. he hybrid

protein, which forms spherical particles !!nm in diameter, elicited levels of neutrali0ingantibodies against foot and mouth disease virus that were at least a hundred times greater

than those produced by the monomeric peptide.

!mmuni6ation and 7erd !mmunity

he following uestions should be asked when a vaccination policy against a particularvirus is being developed.

. What proportion of the population should be immuni0ed to achieve eradication.

!. What is the best age to immuni0eE

#. How is this affected by birth rates and other factors

%. How does immuni0ation affect the age distribution of susceptible individuals,

particularly those in age-classes most at risk of serious diseaseE

'. How significant are genetic, social, or spatial heterogeneities in susceptibility to

infectionE

). How does this affect herd immunityE


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( basic concept is that of the basic rate of the infection & =. for most viral infections, & = is

the average number of secondary cases produced by a primary case in a wholly susceptible population. 8learly, an infection cannot maintain itself or spread if & = is less than . & = can

be estimated from as F2(-*3; G life e/pectancy, ( G average age at which infection is

acuired, * G the characteristic duration of maternal antibodies.

he larger the value of & =, the harder it is to eradicate the infection from the community inuestion. ( rough estimate of the level of immuni0ation coverage reuired can be estimated

in the following manner4 eradication will be achieved if the proportion immuni0ed e/ceeds

a critical value pinc G -F& =. hus the larger the & =, the higher the coverage is reuired to

eliminate the infection. hus the global eradication of measles, with its & = of = to != ormore, is almost sure to be more difficult to eradicate than smallpo/, with its estimated & = of

! to %. (nother e/ample is rubella and measles immuni0ation in the :$. &ubella 2( G C

years3 has an &o roughly half that of measles 2( G ' years3 and indeed rubella has beeneffectively eradicated in the :$ while the incidence of measles have declined more slowly.

Why do we not reuire == coverage to eradicate an infectionE 5mmuni0ation has both adirect and indirect effect. he susceptible host population is reduced by mass immuni0ation

so that the transmission of infection has become correspondingly less efficient andeventually, the infection will be unable to maintain itself.

Average age

of infection

Epidemic

period

R0 Critical

coverage

7easles %-' ! '-1 C!-C'

ertussis %-' #-% '-1 C!-C'

7umps )-1 # =-! C=-C!

&ubella C-= #-' 1-6 6'-61

*iptheria -% %-) '-) 6=-6'olio !-' #-' '-) 6=-6'

1. Different Types of Vaccine

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