Secondary measles vaccine failures identified by
measurement of IgG avidity: high occurrence among teenagers vaccinated at a
young age.
Paunio M, Hedman K, Davidkin I, Valle M, Heinonen OP, Leinikki P, Salmi A,
Peltola H.
Department of Public Health, University of Helsinki, Finland.
Failure to seroconvert (primary vaccine failure) is believed to be the
principal reason (approx. > 95%) why some vaccinees remain susceptible to
measles and is often attributed to the persistence of maternal antibodies in
children vaccinated at a young age. Avidity testing is able to separate
primary from secondary vaccine failures (waning and/or incomplete immunity),
but has not been utilized in measles epidemiology. Low-avidity (LA) and
high-avidity (HA) virus-specific IgG antibodies indicate primary and secondary
failure, respectively. Measles vaccine failures (n = 142; mean age 10.1 years,
range 2-22 years) from an outbreak in 1988-9 in Finland were tested for
measles-virus IgG avidity using a protein denaturating EIA. Severity of
measles was recorded in 89 failures and 169 non-vaccinees (mean age 16.2
years, range 2-22 years). The patients
with HA antibodies (n = 28) tended to have clinically mild measles and rapid
IgG
response. Among failures vaccinated at < 12, 12-15 and > 15 months of
age with single doses of Schwarz-strain vaccine in the 1970s, 50 (95% CI
1-99), 36 (CI 16-56) and 25% (CI 8-42) had HA antibodies, respectively. When a
single measles, mumps and rubella (MMR) vaccine had been given after 1982 at
15 months of age, only 7% (CI 0-14) showed HA antibodies. Omitting re-vaccinees
and those vaccinated at < 15 months, Schwarz-strain recipients had 3.6 (CI
1.1-11.5) higher occurrence of HA responses compared to MMR recipients. Apart
from one municipality, where even re-vaccinees had high risk of primary
infection, 89% (CI 69 to approximately 100) of the infected re-vaccinees had
an HA response. Secondary measles-vaccine failures are more common than was
more previously thought, particularly among individuals vaccinated in early
life, long ago, and among re-vaccinees. Waning immunity even among individuals
vaccinated after 15 months of age, without the boosting effect of natural
infections should be considered a relevant possibility in future planning of
vaccination against measles.
Atypical measles in a patient twice vaccinated against
measles: transmission from an unvaccinated household contact.
Artimos de Oliveira S, Jin L, Siqueira MM, Cohen BJ.
Department of Infectious Diseases, Hospital Universitario Antonio Pedro, Rua
Marques do Parana, 303, 2o. andar, RJ 24030-210, Niteroi, Brazil. artimos@nitnet.com.br
Described are two cases within the same household that were involved in an
outbreak of measles in Niteroi, RJ. Measles diagnosis was confirmed
serologically by specific IgM detection in Case 1 (classic measles) who was
unvaccinated, and rising measles specific IgG in the absence of IgM in Case 2
(mild modified measles) who had a
history of two vaccinations with measles-containing vaccines. Measles
virus was detected by reverse transcriptase polymerase chain reaction (RT-PCR)
in saliva samples from both cases. The nucleic acid amplified by RT-PCR was
sequenced and showed identical measles sequence in the two cases. This study
highlights the difficulty of diagnosing nonclassical measles infection on
clinical and serological grounds, and the usefulness of PCR for viral RNA
sequencing from noninvasive specimens for confirming epidemiologic links.
MRC Laboratories, Fajara, Banjul, The Gambia. whittle@commit.gm
BACKGROUND: Despite a high coverage
with measles vaccines in parts of west Africa, epidemics of measles occur with
reduced severity in an increasing proportion of older children who have been
vaccinated. We examined the effect of exposure to natural measles on
immunity in vaccinated children. METHODS: Our study was carried out in 1992
during an epidemic of measles in Niakhar, a rural area of Senegal with about
27,000 inhabitants who mostly live in compounds that include several
households; within each household people live in different huts. Vaccine
coverage in Niakhar was 81% at the time of our study. We measured
haemagglutinin-inhibiting antibody at exposure and twice thereafter (after 4-5
weeks and at 6 months) in 36 vaccinated and 87 unvaccinated children. The
frequency of measles and subclinical measles--defined as a four-fold or
greater rise in antibody titre without clinical signs or symptoms--was related
to intensity of exposure according to whether the index case was in the same
hut, household, or compound. FINDINGS: Clinical measles occurred in 20 (56%)
of 36 unvaccinated children and in one (1%) of 87 vaccinated children.
Subclinical measles occurred in 39
(45%) of 86 vaccinated children who were exposed to measles and in four (25%)
of 16 unvaccinated children. The frequency was inversely related to
pre-exposure antibody concentration (p<0.001 for trend) and directly related
to intensity of exposure (p=0.002 for trend). Antibody concentrations in
subclinical cases increased on average by 45-fold and remained raised for at
least 6 months. INTERPRETATION:
Increased antibody titre
after subclinical measles may be common in vaccinated children in West Africa
where the intensity of exposure is high. As measles vaccination
coverage increases, the circulation of wild measles will decrease, and
vaccine-induced antibody is less likely to be boosted.
Thus, new epidemics, albeit milder in
form, may occur in vaccinated areas which should be recognised
in campaigns to eradicate measles.
Isolation of measles virus from a naturally-immune,
asymptomatically re-infected individual.
Vardas E, Kreis S.
National Institute for Virology, Sandringham, South Africa.
BACKGROUND: The changing epidemiology
of measles with mild measles cases increasingly being recognised
in previously-vaccinated individuals, suggests that more asymptomatic or
subclinical cases might be occurring. Although this has been clearly
documented in previously-vaccinated individuals, the frequency of these
asymptomatic infections in individuals previously naturally-infected with
measles is not known. Also, it is not known whether these asymptomatic or
mildly-infected individuals who do not display the full range of clinical
signs of measles are capable of transmitting the virus to other susceptible
persons. OBJECTIVES: To demonstrate the isolation of measles virus (MV) from
previously, naturally-immune individuals asymptomatically infected with
measles while in close contact with acutely infected family members and to
document the secondary immune responses (SIR) associated with asymptomatic
measles infection. STUDY DESIGN: Throat swab and urine specimens from five
acute measles cases and their family contacts, taken within 5 days of onset of
rash in each acute case, were used to isolate MV by tissue culture. Positive
tissue culture results were confirmed by indirect immunofluorescence (IF)
staining. Measles specific antibodies (IgG and IgM), IgG urea avidity and
measles-neutralising antibodies were measured in the one family (index family)
where an asymptomatic measles infection of a contact was demonstrated.
RESULTS: The acutely infected patient in the index family (T1/96) had a
measles-neutralising antibody titre of < 1:10, measles IgG urea avidity of 24%
and MV was isolated and confirmed by IF from urine and throat swab specimens.
T1/96 represents acute measles infection after primary vaccine failure because
he had a clear history of being vaccinated against measles as a child. MV was
also successfully isolated from throat swab and urine specimens from the other
four acute cases and from the urine but not the throat swab of an
asymptomatically infected family contact in the index family (mother, T2/96).
T2/96 had a history of natural measles infection as a child approximately 50
years ago. In addition to detectable MV in urine this contact also had a SIR
with a rise in measles specific neutralising antibody titre. No virus was
isolated from the other contact in the index family (father, T3/96) or from
the contacts of the other four acute cases examined. CONCLUSIONS: This is the
first report of a confirmed asymptomatic MV infection, by MV isolation and IF
testing and a concurrent SIR, in a previously naturally-immune contact of an
acute case. The importance of these findings to the epidemiology and control
of MV as well as the diagnostic value of MV urine isolation and IF
confirmation for mild or asymptomatic cases must be examined further.
Department of Biological Sciences, University of Warwick, Conventry, England.
An increasing body of evidence
suggests that a substantial proportion of individuals who respond to measles
vaccine display an antibody boost accompanied by mild or no symptoms on
exposure to wild virus. It is unknown whether this emerging class of
individuals can support transmission. The epidemiologic consequences of
vaccinated individuals able to transmit virus are investigated using a
mathematical model. Parameters for this model are estimated using regression
analysis on a Canadian serologic data set. The authors confirm that
neutralizing antibodies are decaying significantly in absence of circulating
virus. Based on a protective threshold plaque reduction neutralization (PRN)
titer of 120, the authors estimate the mean duration of vaccine-induced
protection in absence of reexposure to be 25 years (95% confidence interval
(CI) 18, 48). After long-term absence of circulating virus, the mathematical
model predicts that 80% (95% CI 65, 91) of all seroconverted vaccinees have
titers below the protective threshold. In this case, elimination of measles
virus cannot be achieved by a single-dose routine vaccination strategy if the
basic reproduction number in vaccinated individuals exceeds 1.24 (95% CI 1.10,
1.53). For this reason, there is a need to establish the intensity and
duration of infectiousness in vaccinated individuals.
Acute and long-term changes in T-lymphocyte subsets in
response to clinical and subclinical measles. A community study from rural
Senegal.
Lisse I, Samb B, Whittle H, Jensen H, Soumare M, Simondon F, Aaby P.
Department of Pathology, Hvidovre Hospital, Denmark.
To investigate the possibility of long-term suppression of T-lymphocyte
subsets, we examined children exposed to measles at home during an epidemic in
rural Senegal, at time of exposure and 1 and 6 months later. The measles case
fatality ratio was 1%. Subclinical
measles was common among vaccinated children exposed to measles (45%).
Both clinical and subclinical cases of measles showed a significant rise in
absolute CD4 count in the incubation period. In the prodromal phase and the
first week after the rash, the lymphocyte percentage, the white blood cell
count and the absolute CD4 cell numbers were significantly reduced. There was
no persistent decrease of absolute CD4 or CD8 numbers at 1 or 6 months after
exposure. Measles infection was followed by significant changes in the subset
composition, both CD4 and CD8 percentages being significantly higher in the
second month after measles than among non-seroresponders. These changes were
more marked among girls, since they had significantly higher CD4 percentages
and CD4/CD8 ratios than boys in the convalescence phase. In conclusion,
measles infection is not associated with a long-term suppression of CD4+ or
CD8+ T-lymphocytes.
Estimated susceptibility to asymptomatic secondary immune
response against measles in late convalescent and vaccinated persons.
Damien B, Huiss S, Schneider F, Muller CP.
Laboratoire National de Sante, Luxembourg, Germany.
Serological evidence indicates that measles virus (MV) could circulate in
seropositive, fully protected populations.
Among individuals fully protected
against disease, those prone to asymptomatic secondary immune response are the
most likely to support subclinical MV transmission. The serological
characteristics of protected subjects who developed secondary immune response
after reexposure to measles have been described recently [Huiss et al. (1997):
Clinical and Experimental Immunology 109:416-420]. On the basis of these data,
a threshold of susceptibility was defined to estimate frequencies of secondary
immune response competence in different populations. Among measles, late
convalescent adults (n = 277) and vaccinated high school children (n = 368),
3.2-3.9% and 22.2-33.2%, respectively, were considered susceptible to
secondary immune response. A second vaccination did not seem to lower this
incidence. Even when estimates of
symptomatic secondary immune response (e.g., secondary vaccine failure) were
taken into account, susceptibility to subclinical secondary immune response
was still 5-8 times higher after vaccination than after natural infection.
Although viral transmission between protected individuals has never
been directly demonstrated, the data describe a population in which protected
but infectious persons could potentially be of epidemiological importance.
[The cell-mediated response after measles vaccination]
[Article in Italian]
Pala S, Crimaldi G, Consolini R, Macchia P.
Istituto di Clinica Pediatrica, Universita di Pisa, Italia.
Natural measles virus infection is recognized for causing prolonged
abnormalities in immune responses, that contribute to the severe and
complicated evolution of the disease. Immunization
with live measles virus vaccine could be considered a mild form of the measles
infection. Results of investigation of in vitro immune response after
measles immunization with live attenuate vaccine have been conflicting. In
this work we studied cellular immune parameters in children aged between 3 and
12 years. T cells, CD4+ and CD8+ subsets were analyzed by cytometry. CD3+
cells were significantly reduced compared to controls (p < 0.01) whereas
CD4+/CD8+ ratio was normal. The in vitro proliferative response to polyclonal
mitogen was significantly reduced (p < 0.01). This study confirms the presence
of a mainly functional immunosuppression of cellular response in a cohort of
children belonging to a developed area. These findings improve the
understanding of the mechanism of immune response to virus measles and provide
suggestions for the development of a better approach to immunization, taking
account for the strain, vaccine titre, age and environmental conditions of the
target population.
Nonclassic measles infections in an immune population
exposed to measles during a college bus trip.
Helfand RF, Kim DK, Gary HE Jr, Edwards GL, Bisson GP, Papania MJ, Heath JL,
Schaff DL, Bellini WJ, Redd SC, Anderson LJ.
Emory University, Division of Viral and Rickettsial Diseases, National Center
for Infectious Diseases, Atlanta, Georgia, USA.
This study investigated the frequency of mild or asymptomatic measles
infections among 44 persons exposed to a student with measles during a 3-day
bus trip using two buses. Questionnaires and serum samples were obtained 26-37
days after the trip. All participants had detectable measles-neutralizing
antibodies, and none developed classic measles symptoms. Ten persons (23%)
were IgM positive for measles, indicating recent infection. Among previously
vaccinated IgM-negative persons, those who rode on bus A with the index
case-patient had significantly higher microneutralization titers than those on
bus B (P= .001), suggesting that some persons on bus A were infected but were
IgM negative at the time of the study.
Mild or asymptomatic measles infections are probably very common among
measles-immune persons exposed to measles cases and may be the most common
manifestation of measles during outbreaks in highly immune populations.
Characteristics of asymptomatic secondary immune responses
to measles virus in late convalescent donors.
Huiss S, Damien B, Schneider F, Muller CP.
Department of Immunology, Laboratoire National de Sante, Luxembourg,
Luxembourg.
Among 44 fully protected, late
convalescent adults re-exposed to measles, four developed an asymptomatic
secondary immune response (SIR) with a significant increase in measles virus
(MV)-specific IgG
and low IgM. The boosted antibodies were mainly of the IgG1 subclass
and reacted with the nucleoprotein and the haemagglutinin protein. About 30
weeks after re-exposure, antibody levels had decreased by 35-50%, suggesting
that the booster effect may only be transient. SIR was only found in
individuals with a pre-exposure IgG level below a well defined threshold.
Antibody levels above this threshold fully protected against SIR. SIR seems to
be an 'all or none response' where the magnitude of increase in specific IgG
is independent of pre-exposure antibody levels as long as these are below the
above threshold. In combination with pre-exposure neutralizing and
haemagglutination inhibiting titres, a threshold was defined below which SIR
is likely to occur. This may be useful to predict susceptibility to SIR in a
given population, since individuals undergoing clinically inapparent SIR are
among seropositive subjects, the most likely candidates to support
transmission of virus.
Five cases of measles secondary vaccine failure with
confirmed seroconversion after live measles vaccination.
Hirose M, Hidaka Y, Miyazaki C, Ueda K, Yoshikawa H.
Hirose Children's Clinic, Saga, Japan.
We report 5 patients with secondary vaccine failure (SVF) who were infected
with natural measles 2, 5, 5, 7 and 12 years, respectively, after vaccination
with further attenuated live measles vaccine during infancy. Their
seroconversion had been confirmed after vaccination.
Three of the 5 patients had mild
(modified) measles, while the remaining 2 patients had typical measles.
The hemagglutination inhibition antibody titers to measles virus in paired
acute and convalescent sera showed a secondary response pattern in 4/5
patients, and a primary response pattern was present in the remaining patient.
Measles IgM antibodies were present in all patients during the convalescent
stage. The patient with the primary response pattern may have had a decrease
in the B cell memory during the 5-year period between vaccination and
infection. This may be the first SVF case report that confirms the existence
of completely waning immunity in recipients of the further attenuated live
measles vaccines.
[Study on the subclinical infection of the recipients of
measles vaccine]
[Article in Chinese]
Wu T, Wang SL, Xiang YZ.
Sanitary and Anti-epidemic Station, Zhejiang Province, Hangzhou.
Through observation to subclinical
infection of the 71 children who had been inoculated against measles 12 years
ago and then exposed to natural measles from three classes at a primary
school, we have noticed: (1) Subclinical infection did exist among the crowd
who were inoculation against measles; The rate of subclinical infection of the
three classes was between 18.5%-75.0%, with an average of 45.1%. (2)
The level of the HI Ab titer was between 1:2-1:16. The peak level was between
1:2 and/or 1:4. So the rate of subclinical infection who had been inoculation
against measles but later exposed to natural measles would depend on the
proportion of those whose titer of HI Ab was 1:2-1:4 in the crowd. (3) The
epidemiological significance of subclinical measles infection lies in that it
can actively keep and consolidate the level of immunity to certain extent in a
crowd who had been inoculation against measles.
[Mumps vaccines: vaccination failures from an immunological
viewpoint]
[Article in German]
Hess U.
Bundesamt fur Gesundheitswesen, Bern.
The significance of mucosal and systemic immunity is illustrated with the
example of the different immune response of Poliovaccine live oral (Sabin) and
Poliovaccine inactivated parenteral (Salk).
On the occasion of rubella- and
measles-outbreaks it will be demonstrated that in vaccinated people
subclinical reinfections
may much more frequently occur than clinically manifest diseases. On
the basis of these findings one may consider the large number of parotitis
cases without complications in mumps vaccinated Swiss pupils as secondary
mucosal vaccine failures at a time, when systemic immunity still was
protective. Significance for vaccination policy and consequences for handling
of vaccines shall be briefly discussed.
Department of Epidemiology, Statens Seruminstitut, Copenhagen, Denmark.
The impact of exposure to measles before 6 months of age has been investigated
by comparing survival to 5 years of age for exposed children and controls in
an urban (Bandim) and a rural (Quinhamel) area of Guinea-Bissau. In Bandim,
cumulative mortality from time of exposure to age 5 years was 34.4% among
exposed children and 9.3% among controls. In a matched pair analysis, exposed
children had a mortality ratio (MR) of 3.80 (95% confidence interval [CI]:
1.42-10.18) compared with controls. In an unpaired analysis using Cox'
regression model to standardize for background variables (sex, measles
infection, age at exposure, exposure from own household, measles vaccination),
there was little change in the MR (3.84, CI: 1.55-9.48). Even after 2 years of
age, the exposed children tended to have higher mortality (MR = 7.96, CI:
0.98-64.74). In the rural area, the MR between exposed children and controls
was 11.39 (CI: 1.42-91.51). Limited
serological data suggest that at least some of the exposed had subclinical
measles. In the urban area, where two studies of early exposure have
been carried out, excess mortality among exposed children corresponds to 40%
and 52%, respectively, of the acute measles mortality. Since these deaths
would not be associated with measles in a study of protection against death
after vaccination, measles immunization may have a much greater effect on
childhood mortality than has previously been assumed.
The present article illustrates the extent of secondary vaccine failure after
vaccination for measles, mumps and rubella (MMR). Secondary vaccine failure
means loss of the immunity induced by vaccination to such an extent that
infection becomes possible. Serological investigations carried out with
follow-up periods of up to 16 years after vaccination for measles, 21 years
after vaccination for rubella and 12 years after vaccination for mumps reveal
that loss of antibodies occurs with the elapse of time but that the clinical
significance of this is probably very limited. Where all three types of
vaccination are concerned, secondary vaccine failure has hitherto been very
seldom. Infection with measles after
secondary vaccine failure is generally described as running a milder course.
In rare cases, rubella re-infection has resulted in infection in utero,
so that a slight risk of congenital rubella cannot be entirely excluded after
successful vaccination. No extensive systematic investigations of the effect
of revaccination have been carried out and, similarly, the optimal interval
between two or more vaccinations has not been illustrated in more detail in
the literature. Subclinical infection
is not uncommon after all three vaccines. Where measles is concerned,
immunity may possibly be regarded as a continuum which, depending upon the
antibody level, protects the individual from various degrees of clinical
disease. If wild virus can be spread via individuals with subclinical
infections, it is doubtful whether population immunity (herd immunity), which
is necessary to eliminate the three diseases, can be attained in large
populations.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Microbiology and Immunology, Faculty of Medicine, Ain Shams
University, Cairo, Egypt.
The present study was designed to estimate the level of measles IgG antibody
in infants early after vaccination and in preschool children to determine
their immune status. Three groups were studied: Group I, unvaccinated infants,
Group II, recently vaccinated infants and Group III vaccinated preschool
children. Measles IgG antibody was measured using the ELISA technique. The
study showed that 90% (18/20) of the unvaccinated Group I infants were
seronegative and only 10% were seropositive for measles IgG antibody
representing most probably persisting maternal antibodies. Fifty percent
(15/30) of recently vaccinated Group II infants were seropositive. A
statistically significant higher antibody level was observed in Group II
infants in comparison to those of Group I. The majority of seropositive
infants of Group II (10/15 = 66.7%) showed high antibody level representing
successful vaccination. Seropositives represented 77.4% (24/31) of Group III
preschool children and the majority of them 75% (18/24) showed high antibody
level which was significantly higher than the comparable in Group II infants,
most probably due to subclinical
infection in addition to successful vaccination. Fifty percent (15/30)
of Group II infants and 22.6% (7/31) of Group III children were seronegative,
more likely due to failure of initial vaccination.
Duration of immunity following immunization with live
measles vaccine: 15 years of observation in Zhejiang Province, China.
Dai B, Chen ZH, Liu QC, Wu T, Guo CY, Wang XZ, Fang HH, Xiang YZ.
National Institute for the Control of Pharmaceutical and Biological Products,
Temple of Heaven, Beijing, China.
The duration of immunity following measles vaccination of 2882 immunized
children has been investigated in a closed region of China for 15 years. A
total of 1002 of the children were treated as primary immunization subjects,
and 1547 as reimmunization subjects. These two cohorts were not in contact
with known wild measles virus over the whole observation period, and the
results obtained probably reflected the antibody responses to measles vaccine
alone. The remaining 333 vaccinees
came into contact with wild measles virus, and this permitted evaluation of
the protective effect of the measles vaccines tested: 4 children experienced
very mild clinical measles, and 329 experienced subclinical infection,
including 12 who had had undetectable haemagglutination-inhibition antibodies
for 9-10 years. These results indicate that the immunity induced by successful
primary immunization may persist for at least 15 years. Within this period, a
second dose of vaccine only induces low antibody responses which decrease
rapidly to their original levels. This provides strong evidence that the
immunity produced by primary immunization is long-lasting. However, there were
some indications that reimmunization might produce better effects if live
attenuated measles virus were used with a longer interval between doses.
Department of Pediatrics, University of Wisconsin, Madison 53792.
A prolonged school-based outbreak of measles provided an opportunity to study
"vaccine-modified" mild measles and secondary vaccine failure. Thirty-six
(97%) of 37 unvaccinated patients had rash illnesses that met the Centers for
Disease Control clinical case definition of measles, but 29 (15%) of 198
vaccinated patients did not, primarily because of low-grade or absent fever.
Of 122 patients with seroconfirmed measles, 10 patients (all previously
vaccinated) had no detectable measles-specific IgM and significantly milder
illness than either vaccinated or unvaccinated patients with IgM-positive
serum. Of 108 vaccinated patients with seroconfirmed measles, 17 patients
(16%) had IgM-negative serology or rash illnesses that failed to meet the
clinical case definition; their mean age (13 years), age at the time of
vaccination, and time since vaccination did not differ from those of other
vaccinated patients. The occurrence of
secondary vaccine failure and vaccine-modified measles does not appear to be a
major impediment to measles control in the United States but may lead to
underreporting of measles cases and result in overestimation of vaccine
efficacy in highly vaccinated populations.
Subclinical measles infection in vaccinated seropositive
individuals in arctic Greenland.
Pedersen IR, Mordhorst CH, Glikmann G, von Magnus H.
Institute of Medical Microbiology, University of Copenhagen, Denmark.
Measles vaccination was performed in the arctic district of Scoresbysund,
Greenland in 1968, which had never been exposed to natural measles. More than
90% of the total population was vaccinated and a 94-100% seroconversion was
obtained. During a serological survey
to examine the immunity status of the vaccinees,
it was discovered that a temporary increase in measles antibodies took place
in the majority of the population 2-4 years after the vaccination. This was
not accompanied by clinically observed measles. Most likely, it was due to an
inapparent
measles infection in a population considered highly immune after vaccination.
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MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION
PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS
OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR
LEGAL ADVICE. THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND
COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH
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