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Jacob M. Puliyel MD MRCP
Issues and Controversies in Contemporary Immunisation
Jacob M. Puliyel MD MRCP
Head of Department
Department of Pediatrics
St Stephen's Hospital
Tis Hazari
Delhi 110054
Email [log in to unmask]
Kishore S. Agarwal MBBS DCH
Registrar Department of Pediatrics
St Stephen's Hospital
Tis Hazari
Delhi 110054
VIGNETTE FROM HISTORY
A LESSON IN TWO PARTS
The Jenner Story
On the basis of anecdotal evidence, Edward Jenner conducted this bizarre
experiment. He extracted fluid from the pustule of a girl with cowpox and
injected this intradermally in a healthy 8-year-old called James Phipps. 6
weeks later he deliberately exposed this young lad to small pox. Fortunately
the boy did not get small pox (1). This was in May 1796
Jenner wrote about this experiment and sent it for publication in the
Philosophical Transactions of the Royal Society. Sir John Banks the
President of the Royal Society rejected the manuscript. He also warned
Jenner that he had better not promulgate such wild ideas if he valued his
reputation. (2)
200 years after the vaccination of James Phipps the last case of naturally
acquired small pox was noted on 26 October 1977 in a Somali village in Ali
Maow Marlin.
To digress a bit, it is worth mentioning that there were 2 more deaths
after that, related to small pox. In 1978, injudicious manipulation of the
small pox virus, in the Medical School of the University of Birmingham, led
to the death of Janet Parker, a medical photographer and to the subsequent
suicide by Prof. Henry S. Bedson, Head of the Department of Medical
Microbiology of that hospital (1).
The dramatic vanquishing of one of humankind's greatest scourges evoked
hopes of the conquest of other diseases as well, through immunisation.
Hopes are so high that a certain misplaced cockiness has crept in. Vaccines
are a powerful double-edged tool with both risks and benefits and these need
to be monitored constantly. The fiasco with the high titer Edmonston-Zagreb
measles vaccine, given at the age of 6 months, illustrates how this form of
monitoring is vital to detecting subtle vaccine induced risks.
The Edmonston-Zagreb Fiasco
Ideally, vaccine experts like to wait until 12 to 15 months of age to give
the measles vaccine. At this age children no longer have any maternal
antibody which can interfere with the response to the vaccine. However some
children in developing countries become susceptible from 4-6 months of age.
The high titer Edmonston-Zagreb (EZ-HT) measles vaccine given as early as 4
to 6 months, produced less vaccine failures and provided clinical protection
(3-5).
In 1989 WHO recommended the use of EZ-HT measles vaccine at the age of 6
months in areas with high incidence and high mortality from measles before 9
months of age (6). The long term impact on mortality had not been examined
when this recommendation was made.
Long-term follow-up to the age of 3 to 4 years in a study in Bissau using
the EZ-HT found mortality for female recipients of the high titer EZ was two
times higher, compared to female recipients of the standard Schwarz measles
vaccine (7). Another study from Senegal showed the same thing (8). However
an international expert panel decided that the evidence was unconvincing
(9). The higher mortality in female recipients of the high titer vaccine
was then seen in Haiti (10). Given the biologically implausible but
reproducible observation, a second expert panel recommended the high titer
measles vaccine no longer be used (11). The WHO would not have been in this
awkward position had it checked on the long-term impact of the new vaccine
before making its recommendation. Relatively small changes in vaccine
potency or timing can make a lot of difference to the risk benefit equation.
WHAT TO EXPECT IN THIS CHAPTER
In this chapter we will look at some general principles of vaccination and
risk benefit analysis. We will then look at individual vaccines. The
controversies are viewed, from the scientific and the socio-economic angles.
Then there is a rather lengthy discussion on cost effectiveness estimations.
Readers who are not interested in those details may skip this section and go
on to the next section, on vaccination and the law. Finally we look into the
future with its hopes and pitfalls.
In the space of this chapter we have not been able to deal exhaustively with
all the issues and controversies related to immunisation. With the broad
issues raised we hope only to be thought provoking. The chapter is written
from the standpoint of India as a developing country.
General Principles
Generally speaking attenuated live organisms are more effective than
inactivated or killed preparations. Live attenuated vaccines have better
ability to induce long-lasting immunity and to stimulate cell mediated
immunity in addition to humoral immunity. They suffer from a tendency to
adverse reactions such as reversion to wild type parental strain. Killed
vaccines are non-infectious but need booster injections due to shorter
periods of protective immunity (12).
Sabin's law states that "a live genetically-engineered, safe, deletion
mutant cannot be expected to do more than natural infection with the
unmodified virus". Vaccines like the Haemophilus Influenza B conjugate
vaccine, which stimulates immunity, better than natural infection have
proved this law wrong (13).
Risk Benefit Ratio
The risk benefit ratio is a dynamic mathematical solution to the question
of, is the cure (prevention) worse than the disease".
1. Let 'a' represent the life time risk of an individual getting the
disease in the community
(Usually given as a fraction, say 1 in a 1000.)
2. Let 'b' represent the fraction of those with disease, likely to develop
a serious complication
(Usually given as fractions say 1 in 100 or 1 in 1000 etc.)
3. Let 'x' represent the fraction of those vaccinates who develop a serious
complication due to the vaccine.
4. Then 'a' multiplied by 'b' represents - Benefit
And 'x' represents the - Risk
If 'x' is greater than 'a' multiplied by 'b' - the vaccine should not be
used, as the risk of vaccine related complication, is more than the risk of
acquiring the disease in the community and getting a serious complication
from it.
Assume that 1 in ten of the population develops measles.
Assume 1 in a thousand of those with measles develop Subacute Sclerosing
Panencephalitis (SSPE).
Then the chance of SSPE is 1/10 ('a') multiplied 1/1000 ('b') = 1/10,000.
Suppose 1 in a 100,000 of those who receive measles vaccine develop SSPE
then the risk 'x' is 1/100,000
The benefit is higher than the risk.
The factor 'x' remains constant for any given vaccine.
The factor 'b' remains constant for a given illness.
However the factor 'a' is different in different populations and changes
with time.
The chance of getting Hepatitis A much lower in Europe than in Asia. Thus,
with its good sanitation, the vaccine risk may be too high for Europe but
acceptable for its benefits in Asia. Small pox risk is an example of how
time alters the risk benefit ratio (14). As long as small pox was epidemic,
the risks of disease were more, compared to the risks of vaccination.
However after small pox was eradicated, the risk of continuing with that
vaccination programme became unacceptably high compared to risk from the
disease. The same is the problem with vaccine induced Polio in developed
countries, where the risk of acquiring wild polio is now nearly eliminated
(15).
To this simple formula refinements may be incorporated. For a vaccine that
has a very limited duration of protection, for example Viral Influenza
vaccination that must be given each year, instead of life time risk, the
risk of the acquiring the disease each year, may be considered.
A vaccine does not protect all those vaccinated. Suppose the vaccine
protects 1 in 2 of those vaccinated, the benefit is reduced, and must be
multiplied by a fraction 'c' = 1/2 in this case
'a' multiplied 'b' multiplied 'c' must be greater than 'x'.
Polio vaccine
As this chapter comes out of the press, we would be near 1 July 2000, when
polio should be eradicated from the world. Oral live polio vaccine has been
used extensively in this programme. In countries like the USA wild polio
has been eliminated (16) but there is likely to be about 9 cases of vaccine
associated paralytic polio (VAPP) if Oral Polio Vaccine alone continues to
be used (17.18). A sequential inactivated polio virus (IPV) and oral polio
vaccine (OPV) schedule is therefor recommended there. 2 doses of the
injectable killed polio vaccine (IPV) are given at 2 month and 4 months.
This is followed by OPV at 12-18 months and 4 to 6 years. This combined
schedule is thought to eliminate disease in the vaccine recipient and
provide gastrointestinal immunity. However cost effectiveness analysis done
in the USA suggests that inclusion of IPV would cost between $ 1.7 million
and $ 11.2 million for each case of VAPP prevented! (15). It has been
justified in the hope that after the global eradication of poliovirus in the
year 2000, vaccination may be discontinued. It is interesting also to note
that America aid to developing countries for their vaccination programmes
has this potential of reducing costs of their own vaccination programme.
Like Shakespeare said about the quality of mercy -'It blesseth him that
gives and him that takes.'
While on the subject of polio vaccine and its dangers, it is worth noting
that between 1955 and 1963 tens of millions of American were vaccinated with
an IPV grown in monkey kidney cells, contaminated with live Simian Virus 40
(SV40), which is tumerogenic in rodent and recently detected in several rare
human tumors including ependymomas, osteosarcomas and mesotheliomas. Follow
up 30 years later suggest that exposure to SV40 contaminated polio virus
vaccine was not associated with significantly increased rates of ependymomas
and other brain cancers, osteosarcomes or mesotheliomas in the USA. (19)
BCG
BCG is a vaccine that has had its fair share of controversy. A large
control study done in Chingleput found no difference in the incidence of
pulmonary Tuberculosis (TB) among those vaccinated and those who were not
vaccinated (20) and that report was thought to have sealed the fate of BCG.
The investigators were however barking up the wrong tree. It was later
pointed out that just as full-fledged primary tuberculosis does not protect
from later reactivated tuberculosis, it couldn't be expected that BCG would
reduce the incidence of pulmonary TB. However in primary infection there is
a period of about 3 weeks, before the body gets sensitised to the bacteria,
when there is bacillaemia and seeding foci spread from the primary focus.
It is felt that most cases of tubercular meningitis develop from such
seedling foci. BCG could act by sensitising the body to tuberculosis even
before the initial infection and prevent the phase of bacillaemia and reduce
the incidence of tubercular meningitis (21,22). It has however been noted
that in general, the efficacy of BCG vaccine in any region is proportional
to its distance from the equator and BCG may be least effective in areas of
the world where the risk of tuberculosis is greatest (23).
BCG is credited with other beneficial effects also. It is said to reduce the
risk of leprosy (24) and to retard the development of insulin dependent
diabetes mellitus - probably reflecting a temporary boost of the immune
function after vaccination (25). Immunotherapy with BCG has been tried in
various malignant disorders and is most successful when administered locally
(26).
Measles Vaccine
Reference to the controversy about the high potency measles vaccine has been
made in the introductory paragraphs of this chapter. Overall it is found
that reduction in mortality following immunisation is greater than that
expected simply from a reduction in death from acute measles (27). It is
possible that measles vaccine and natural disease have immunomodulatory
effects. Natural disease may have more pronounced immunomodulatory effect
than the vaccine's attenuated virus. Recovery from natural measles reduces
the incidence of atopy, and allergic reactions to house dust mite, to half
the incidence seen in vaccinated children (28). But this advantage is far
outweighed by the increased mortality from malnutrition and secondary
infections like tuberculosis that is associated with measles infection.
Recently a new syndrome of Ileal-Iymphoid-nodular hyperplasia, non-specific
colitis and pervasive developmental disorder akin to autism has been
reported in 12 children associated with the Measles Mumps Rubella (MMR)
vaccine. In 8 it was noticed within 14 days of receiving MMR vaccination
(29). As yet however, a cause and effect relationship has not been
established conclusively for this association.
Pertussis Vaccine
There has been debate over several years, concerning the perceived link
between pertussis vaccination and brain damage. Anxiety in the mid 1970's,
led to a fall in its acceptance rate for infant immunisation and major
epidemics of 1977-79, 1981-83. (30,31). Since then, confidence has been
restored. In the USA since 1979, 900 children have been awarded vaccine
damage, qualifying as 80% disabled after receiving pertussis vaccination.
This lent impetus to the development of a more safe, acellular vaccine (32).
Acellular pertussis vaccine is however less immunogenic and there is a 50%
decline in antibody titer within one-year (33). This vaccine is also 3 to
10 times more expensive (34). The shift to acellular products would lead to
progressively lower levels of and less durable immunity - unless combated by
more and more booster vaccinations through life. This situation described as
a "Salesman's Dream - and an Epidemiologist's Nightmare"(34)
Meningococcal Vaccine
Meningococal disease is an important epidemic and endemic cause of morbidity
and mortality. Polysaccharide vaccine against A, C, Y and W135 have been
developed but provides a short-term immunity of 3 to 5 years. Their use is
limited to the control of epidemics. They are useful after 2 year of age. It
may be used after 9 months but immunity lasts much less. (35)
Pneumococcal vaccine
The vaccine used in the West is made from polysaccharide capsular antigen of
23 different serotypes. It is not effective below the age of 2 years.
Revaccination is associated with adverse reactions. It is used in patients
before splenectomy or in those with sickle cell disease. Antibodies develop
in 3 weeks and usually lasts 5 years (36).
In India it may be remembered that the IBIS study (37) (Invasive Bacteria
Infection Surveillance) has shown that the most common serotype prevalent
here is Type I (25%), which has disappeared from the West. Serotype 6, which
is the most common serotype in developed countries, caused only 11.5% of
invasive infections in India. A new 11 valent vaccine may cover 76% of
pneunococci in India, but the 23-valent vaccine used abroad, would not be so
useful.
A conjugate vaccine to cover invasive strains in India would be less
effective in neighbouring Bangladesh or Pakistan. A great variation in a
limited area means that, theoretically, vaccination will simply result in
replacement of existing serotypes by non-vaccine sterotypes from adjacent
areas (38).
Routine immunisation with pneumococcal vaccine is not recommended even in
developed countries. It is given to high-risk group. With the different
strains here in India, and the good penicillin sensitivity (nearly100%)(37),
perhaps penicillin prophylaxis may be more useful for these high-risk groups
here, than an expensive vaccine, which yields only a false sense of
security.
Hepatitis A Vaccine
A killed vaccine against Hepatitis A, using the HM 175 strain and
inactivated by formaldehyde is available. 2 doses given 1 month apart are
said to protect for unto 1 year. The vaccine trials began in December 1988
and so we have less than one year's experience with the vaccine. It is
suggested that if a booster dose is administered 6-12 months after the
primary vaccination, then the geometric mean titers of anti HAV will be in
the range of 3000mIU/ml and the manufacturers expect protective levels to
last for 10 years (39).
The world may be divided into areas of high endemicity and others with low
endemicity. In the high endemicity areas, with poor sanitation 30 to 100
clinical cases per 100,000 / year occur. In Jordan close to 100 per cent of
four-year-olds have anti HAV antibodies (40). Only a fraction of these
infants and young children developed a clinical pattern of infection
recognised as hepatitis A. Similarly in Indonesia 95 percent of nine year
old children are naturally immune to HAV (41). Newborn babies carry HAV
antibodies passed on to them before birth, and this gives them immunity to
infection for the first 10-12 months of life. Exposure to HAV results in
development of active immunity in these infants without the symptoms of
clinical infection. They are protected for life. Hepatitis A infection among
adults is very rare in these areas.
Low endemicity areas _ There is a great deal of evidence that improvements
in the standard of hygiene and sanitation are linked to a reduction in
circulation levels of HAV in these countries (42,43)
Thus most people who live in high endemicity areas are protected by their
immune status, due to subclinical infections and people in low endemicity
areas are protected by their water and sanitation systems. Those living in
low endemicity areas however lack anti HAV antibodies and this puts them at
risk when they travel to areas of high endemicity. Thus travel may be an
indication for this vaccine. This is the only indication for use of the
vaccine given in Martindele Extrapharmacopia. (44)
Hepatitis B
Hepatitis B is spread through blood products or sexual intercourse.
Vertical transmission from a carrier mother to infant occurs more commonly
in India while in Europe, most of the spread taken place through sexual
contact in adolescence. Approximately 90% of infection in neonate and young
infant follow a chronic course (45). Only 3 to 10% of adult infection run a
chronic course. (46,47).
Babies born to HbeAg mothers are at very high risk of infection. 66 to 93
percent of untreated babies acquire the infection (45). If vaccinated soon
after birth, at 1 month and 6 months, observed infection is only 3 to 10%.
(48,49)
The Hepatitis B vaccine is relatively free of side effects. A few have
claimed it causes a spectrum of autoimmune and nervous system disorder
including Rheumatoid arthritis, Optic neuritis and neurodegenerative disease
resembling multiplesclerosis (50). A vaccine induced escape mutant hepatitis
virus has been reported in 44 contacts of a Hepatitis B carrier, despite
passive and active immunization (51).
The WHO has recommended universal immunization with Hepatitis B vaccine but
even a developed country like the UK has dragged its feet. They have
calculated a cost of Pounds 188015 and Pounds 301365 per life year gained
depending on duration of program and vaccination strategy (adolescent /
neonatal)(52). Another analysis put the cost of adolescent vaccination at
pounds 51817 and infant vaccination at pounds 94821 per year of life gained
(53).
The majority of transmission in India occurs during the perinatal period
(54). A neonatal vaccination programme must be put in place if the vaccine
program has to be successful in India. Although worthwhile, the vaccine is
out of the reach of those that need it most (55,56). The entry of an
indigenous manufacturer of Hepatitis B vaccine has brought down prices a
little and further reductions may make the vaccine a suitable candidate
vaccine for universal immunization in India, as recommended by the WHO.
Haemophilus Influenza B (Hib)
There is a substantial body of evidence, that humoral antibodies against the
polysaccharide (PRP) capsule of the organism (57) mediate human immunity to
Hib. There is an inverse correlation of disease occurrence and the presence
of specific anticapsular antibodies. Most older children and adults have a
substantial concentration of anticapsular antibodies and do not usually
develop invasive disease. The present understanding is that children under 2
have poor immune response to capsular polysaccharide of Hib. Indeed even
children who develop invasive Hib infections such as meningitis, often do
not develop substantial concentration of serum antibodies, if they are under
18 months of age. Newborns however are protected by maternal antibodies but
the protection is short lived and disappear by the age of 2 months (58). The
conjugation of the PRP with a protein carrier like diptheria toxoid helps to
enhance the immunogenicity of the heptane in children below the age of two.
There is controversy about the titer at which anti Hib polysaccharide yields
protection. Rabbins et al have argued that since invasive Hib is extremely
rare in adults, they must all be having protective concentration of
antibodies. 95% of adult sera analyzed, had more than 0.04 microgram/ml of
anti Hib polysaccharide antibodies and so they concluded that serum levels
of 0.04 to 0.1 microgram/ml affords protection (59). Makela et al found
levels of 0.15 micrograms per ml in adults and used this as the protective
cut off level (60). More pertinently, Santosham et al (61) and Ambrosine et
al (62) tested passive immunoprophylaxis for invasive Hib in high-risk
populations and estimated protective concentration at 0.05 to 0.15
microgram/ml. Thus although the level of 0.15 microgram/ml is widely quoted
as the protective level, levels above 0.05 or 0.1 microgram/ml are probably
sufficient to protect against infection (63).
Against this background we may look at 4 studies that have been done in
India. They have looked at prevaccination levels of Hib antibody titers in
infants and children of different ages and their post Hib vaccination
titers.
In the study done in Delhi (64) the prevaccination geometric mean titer
(GMT) of anti PRP antibodies in 2 sets of 2-month-old infants, were 0.186
and 0.198 microgram/ml. After 3 doses of PRP-tetanus toxoid conjugate
vaccine (PRP-T), the post vaccination level was 18.7 and 13microgram/ml.
This high post vaccination value contrasts with titers of 3.64 to 6.4
microgram/ml observed in other countries (65-68). This suggests that there
is possibly a boosting effect of the high level of antibody found
prevaccination, and that the prevaccination levels are due to actively
acquired immunity by the infant rather than passive immunity from the
mother. The same authors found, in two groups of 2 years old children,
prevaccination geometric mean titre (GMT) levels of 0.25 microgram/ml and
0.210 microgram/ml. Passively acquired antibody levels decline with age.
This study showed higher levels of antibodies in 2 year old children
compared to the level in 2 month-olds. This also suggests that these
children acquired active immunity.
There are three other studies, done in different parts of India, that have
looked at pre-vaccination levels of anti Hib antibodies in small children
(69-71). Protective levels of anti Hib antibodies have been noted
consistently in these studies.
These studies show that infants in India actively produce protective levels
of anti Hib antibodies from very early infancy. Even if no vaccine is
administered the antibody levels rise naturally with time.
As there is nothing to suggest that the strain of Hib found in India is
more immunogenic than that in the west, we must look for another explanation
for these phenomena. The work of Bradshaw et al found other bacteria had
antigen which were cross reactive with the capsular polysaccharide antigen
of Hib. Proof for serologic specificity of the cross reaction was observed
in the precipitate antibody to H.Influenza capsular polysaccharide induced
by immunizing burros with Staphylococcus aureus and Bacillus subtillis (72).
Cross-reactive bacteria such as Staphylococci, Group D Streptococci,
Diphtheroids and E.Coli have been found (73).
In an experiment by Robbins (73) it was found that ordinarily, unconjugated
capsular polysaccharide of H.influnzae type b does not stimulate the
production of antibodies, in infancy. However, the presence of E.coli with
cross-reactive antigen in the gut, enhanced the immune response to H.
Influenzae capsular polysaccharide and caused a rapid and sustained rise in
antibody. E.coli are ubiquitous in developing countries like India.
Whatever the mechanism by which it is achieved, the studies done in India
show that active natural immunity to H.influenzae b develops at an early age
in infants here. There is thus a great potential for savings to be made in
vaccination use, in developing countries, if this finding is further
substantiated.
Cost benefit studies: -
The best studies calculate cost as cost of vaccine (and this may be retail
price or bulk purchase price) (a), and cost of administering the vaccine
(b)(74-76). This should include costs of periodic boosters where needed.
If the vaccine is to be administered along with another immunisation for
which the patient has been scheduled previously, the cost of administering
the new vaccine would be discounted by a factor. The cost of administering
the vaccine de novo includes cost in terms of salaries of doctors and nurses
administering the vaccine, that is cost of professional time taken for
administrating the vaccine (b1), the cost of transportation of vaccine in
the cold chain (b2) and the cost involved to the parents by way of
transportion to the vaccine centre, time off work etc. (b3)
Add to this the costs due to vaccine risk(c). This cost (c) would be the
cost in compensation given to patients who exhibit adverse reaction or it
may be the cost of quality of life years lost due to the reaction.
Finally the better studies have used a calculation for discounting for years
gained in the future (52,53). For any economic evaluation of projects
incurring financial costs and yielding financial benefits after a number
years, it is usual to discount these future benefits at a rate which
reflects the opportunity cost of money (i.e. its alternative use in the
capital market). The UK treasury recommends a 6% discount rate for public
sector projects.
For example, if vaccination of newborns with Hepatitis B costs 1000units
X units) of money. Assume that Hepatitis B vaccine saves money by way of
preventing morbidity from malignancy 20 years later. Assume that the cost
of this malignancy is 2000 units ( Y units ) of money.
( Y ) is greater than ( X ) by a factor of 2 but yet the intervention cannot
be said to be cost effective because if the 1000 units of money ( X ) were
not spend on immunization but put in the capital market at 6% appreciation
per annum, after 20 years it would yield 3207 units of money, which is much
larger than the benefit ( Y ) of 2000 units money achieved 20 years later.
There is controversy about this form of discounting in medical intervention
(75).
Benefits are also calculated by various criteria. For most vaccination
programs, cost per quality adjusted year of life gained is recorded. This is
then compared to cost per quality-adjusted year of life with other accepted
vaccination programs, or even other intervention. Some compare the cost
against cost per quality adjusted year from renal transplantation or breast
cancer screening (52). Such studies done in the West, which prove that an
intervention is cost effective there, cannot be transposed directly to
developing countries, because renal transplants is not considered a cost
effective treatment in many developing nations.
In this discussion it must be remembered that the costs of vaccine
administration are also relatively less in developing countries as cost of
delivery (doctors time etc.) is less. With newer vaccines however, the
major component is the cost of the vaccine itself (76). There is as yet no
mechanism to sell the vaccine in developing countries at a cheaper rate (a
policy of tiered pricing) (75,76) and the price of newer vaccine developing
countries is the same as that in the West although the earning capacity in
developing countries is much less.
Vaccine manufactures argue 'in a chicken and egg fashion' that the world
would be amazed at how rapidly and extensively the prices of the newer
vaccine would fall if sales of 500 million doses per year could be achieved,
particularly for a number of years (77). For Hib this would mean 4 doses to
each year's birth cohort say at two, four, six and 18 months. But because
there is not the global will to reach out as boldly as that, sales will be
very much lower and prices much higher (77). Thus there is a push for
poorer countries to accept these vaccines in an effort to bring down the
prices.
Not all published cost benefit analysis are entirely objective. The Product
Monograph for Varilrix varicella vaccine distributed in India refers to cost
benefit analysis done in the USA (76). The cost of vaccination with Chicken
pox works out at $98 million in the USA. The cost of Chickenpox disease if
no vaccination is used, works out at $ 90 million. Vaccination is thus not
cost effective. Therefore to the saving side, vaccine researchers have added
costs of time which would have to be taken off work by parents of children
with Chickenpox and have concluded that rather than losing $8 million, the
country was actually saving $384 million. It will be noted that chicken pox
is one of the more minor diseases affecting children and it is here that
this devise of adding on the cost of lost work days of the parent has been
invoked. In any case these cost effectiveness studies cannot be assumed to
apply to developing countries as the earnings (and loss, by parents not
being able to go to work for 4 days) are much lower. In the study (76), the
cost of work pay lost by the parent of a child with Chickenpox is said to be
$208 or Rs.8000 (conversion rate of Rs.40 per $). To show the same cost
effectiveness, assuming that parents take 4 days off work for their child's
chicken pox in India(Percapita GNP $390), they must be losing Rs.2000/-day and earning
Rs.60,000/-per month! Thus for vaccination to be as cost effective in India
as it is in the USA, the family must be earning Rs.60, 000/- month.
Vaccine and the Law
There are several legal aspects to mass immunization programs. American
law is the most developed in this respect.
In 1905 the Supreme Court in America held that the municipal law requiring
small pox vaccination of all adults was not a violation of personal liberty
but "among the manifold restraints to which every person is necessarily
subject for the common good"(79).
The law thus recognised the benefits to the community that immunisation
programmes provided and they granted this precedence over personal liberty.
On the other hand the courts made it easy for individuals to claim
compensation from vaccine manufacturers for alleged vaccine injury under
product liability laws. Under strict liability theory (80) it is held that
it is preferable to ease the burden of proof on plaintiffs injured by
defective product and shift the onus onto manufacturers, whose liability
costs ultimately will be distributed equitably among public through the
vehicle of insurance and product pricing. Using this law numerous claims for
vaccine injury were filed. Vaccine manufacturers began to run at a loss and
started withdrawing from the market. This led to a crisis in vaccine supply
in the 1970s(81).
The Childhood Vaccine injury Act 1986 was then enacted. It aims were
twofold:
1. To provide a fair and expeditious legal remedy for children who suffer
from serious sequelae from mandated vaccinations. A 'no fault' compensation
system was instituted. This helped to restore confidence in the mandated
vaccines.
2. To offer greater protection from liability for vaccine administrators and
manufacturers and thus to ensure a safe and secure vaccine supply.
Funding for the vaccine trust fund comes from a surcharge levied against
manufacturers on each dose of vaccine sold.
As of 1997 over 1100 awards have been made to families and individuals
(65).
Similarly in the UK, Crown Indemnity protects doctors administering vaccines
under the National Health Scheme.
In India there are general rulings that lay down that 'certain restraints'
would not constitute a violation of an individual's civil liberties or
fundamental rights and this may be invoked, for compulsory vaccination (82).
The liability for vaccine related injury in India, will at all times rest in
the manufacturer and the relevant statutes, such as the Drugs and Cosmetics
Act 1940, do not even refer to the physician. However under the general
penal code, a physician could be held liable if it could be shown that the
damage was caused by some intervening conduct on the part of the physician
while administering or handling the relevant drug (82).
There is at present no statutory provision in India, which makes the
administration of any drug, the statutory responsibility of the physician.
In contrast to this, a US court has awarded damages to a child with
congenital rubella syndrome, holding the mothers physician responsible for
failure to test and immunise the mother (83).
Vaccines of the future:
1. The cold-adopted influenza virus vaccine uses a strain of influenza virus
that optimally replicates at temperatures lower than 37oC and thus grow well
in the slightly cooler temperature of the nasal passages but cannot cause
disease in the lower respiratory tract (84). The vaccine appears efficacious
inducing mucosal and systemic immune response.
2. Specific mutation deleting the gene that encodes for virulence factor may
be made. Recently an AIDS vaccine has been made (84). It is however
possible that pathogenicity of such a virus could be regained or that
integration of such a virus could have adverse effects such as acting as
cofactor for the development of tumors.
3. A rotavirus vaccine using non-human bovine and monkey strain as a carrier
for reassortment with selected human rotavirus genes have shown initial
promises (85,86).
4. Transgenic potatoes seem capable of producing the antigenic protein whose
gene has been incorporated into their host genome. Transgenic potatoes were
found to produce the binding subunit of cholera toxin in an appropriate form
for antigenicity even after cooking the potato (87).
5. Newer vaccines like Nucleic acid vaccines are on the way. The DNA is
introduced into host cells by a retroviral vector or plasmid vector. Once
taken up by the host cells, the protein subsequently produced in vivo is
exposed to the immune system and stimulates a specific immune response. No
boostering is then required (84).
6. Perhaps the newest and most exciting recent development in vaccine
strategy is the development of vaccines against cancer both for primary
prevention and therapeutic use (88-90). Tumors and cancers arise because
they evade the immune mechanism. Plasmid constructs encoding
carcinoembryonic antigen or artificial tumor antigen have been shown to
elicit alloimmune and protective immune response to tumors expressing the
antigen gene. Promising early results for vaccine against melanoma, breast,
prostatic, pancreatic, colon, cervical and ovarian cancer have been reported
(90).
The lessons of history teach that it is to our peril that we allow the
limitations of our current thinking about disease and its prevention to
determine how we think about disease and its prevention for the future (90).
CONCLUSION
Immunisation has been one of the great successes of 20th century medicine
(90). However with each new vaccine in the market one must ask the questions
1. Is there a need?
2. Does the vaccine yield more good than harm?
3. Is the vaccine cost effective under local conditions?
4. Is it affordable? Even if proven cost effective, the issue about
affordability of the vaccine must be assessed separately
It is interesting to recall in this context, what George Bernard Shaw wrote
about immunisation in1911 (91).
In the Preface on Doctors, in The Doctor's Dilemma under the subheading,
'The Perils of Inoculation' he writes as follows
Suppose it were ascertained that every child in the world could be rendered
absolutely immune from all disease during its entire life time by taking
half an ounce of radium to every pint of its milk. The world would be none
the healthier, because not even a Crown Prince - no, not even the son of a
Chicago Meat King, could afford the treatment. Yet it is doubtful whether
doctors would refrain from prescribing it on that ground. The recklessness
with which they now recommend wintering in Egypt or at Davos to people who
cannot afford to go to Cornwall, and the orders given for champagne jelly
and old port in households where such luxuries must obviously be acquired at
the cost of stinting necessaries, often make one wonder whether it is
possible for a man to go through medical training and retain a spark of
common sense.
Stop press
1.5 million doses of a Rota virus vaccine Rotasheild have been used by 15
July 99. Among them 15 cases of intussesception were noted - 13 developed
symptoms within 1 week of vaccination. USA center for disease control has
advised postponement of vaccine use unto November 99 (92).
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>From
Puliyel
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