The World's First and Only Pneumococcal Conjugate Vaccine
The first vaccine to help prevent pneumococcal
diseases, Prevnar, a conjugated pneumococcal polysaccharide
will be marketed by Wyeth-Ayerst Canada, on January 2001. It targets
the seven serotypes (strains) of pneumococcus that cause more
than 80% of serious pneumococcal disease in North American
S. pneumoniae is an important cause of
morbidity and mortality in persons of all ages worldwide. The
organism causes invasive infections, such as bacteremia and meningitis,
as well as pneumonia and upper respiratory tract infections including
otitis media and sinusitis. In children older than 1 month, S.
pneumoniae is the most common cause of bacteremic disease.
It is estimated there are over one million annual deaths worldwide
caused by this organism in children less than 5 years of age,
mostly due to pneumonia. It is found as the causing organism in
50% of cases with bacterial meningitis, 85% of bacteremia,
66% of bacteremic pneumonia, and 40% of bacterial acute
otitis media among children. In a population - based surveillance
study conducted in Toronto and area from 1995 to 1998, in children
< 16 years old, it was found that the incidence of S. pneumonia
infections was 13.8 cases/100,000/year, and according to age groups
of 0-6 months, and 6-23 months, the average annual incidence was
respectively 23 and 70 per 100,000.
Children who are at increased risk in getting
pneumococcal infections include children with anatomic or functional
asplenia (including those with sickle cell disease), recipients
of chemotherapy, those with congenital and acquired immunodeficiency,
those with chronic renal disease (including nephrotic syndrome),
those with diabetes, with cerebro-spinal fluid leak, and also
children attending out of home care.
Every year in Canada, over half a million cases
of pneumococcal disease are reported in infants and children,
and thousands of Canadian children will undergo ear tube insertion
to treat otitis media. The total annual treatment costs for pneumococcal
disease amounts to nearly 200 million dollars a year. This includes
unscheduled physician visits, surgical interventions and hospitalization.
In addition, pneumococcal disease results in lost work time for
parents due to at-home care for children who miss school or day
care. Increased resistance to penicillin and other important classes
of antimicrobials has complicated the management of S. pneumoniae
infections in recent years. In the study conducted in Toronto,
it was found that 28.5% of isolates were antimicrobial resistant
S. pneumoniae (DRSP) and resistance to >2 antimicrobial
classes ( penicillin and other antibiotics), increased from 10.3%
to 25.3% from 1995 to 1998. Continued reductions in antimicrobial
prescribing and vaccination may have the greatest impact to reduce
infections caused by drug resistant S. pneumoniae.
Approximately 90 serotypes of S. pneumoniae
have been identified based on antigenic differences in their capsular
polysaccharides. The distribution of responsible for disease differs
with age and geographic location. Serotypes 4, 6B, 9V, 14, 18C,
19F, and 23F have been responsible for approximately 80% of
invasive pneumococcal disease in children <6 years old. In
the Toronto study 84.2% of all isolates are included in the
heptavalent pneumococcal conjugate vaccine called Prevnar, which
includes the serotypes previously mentioned.
Bacterial polysaccharides, including those present
on the pneumococcal capsule, are T-independent antigens. Infants
and very young children respond poorly to T-independent antigens.
Immune system response to T-independent antigens requires 2 or
3 years after birth to develop.
Conjugation of polysaccharides to proteins changes
the response to polysaccharide from T-independent to T-dependent.
This antigen complex stimulates a T-helper cell response, leading
to a substantial primary response among infants and stronger booster
response at reexposure.
The vaccine currently in use, licensed in 1983,
contains purified capsular polysaccharide antigen of 23 serotypes
of S. pneumoniae. Although this vaccine has been effective in
reducing severe disease in the adult population, it cannot impact
significantly on the frequency of disease in children <2 years
of age because it does not elicit a significant antibody response
in these children. This vaccine also has not been shown to be
effective in protection against acute otitis media caused by S.
pneumoniae. In contrast, the new conjugated heptavalent pneumococcal
vaccine induces good antibody responses in 90% to 100%
of children to all seven vaccine serotypes, after administration
of 3 doses.
The 7-valent pneumococcal conjugate vaccine (PCV7),
Prevnar (Lederle Laboratories/Wyeth- Ayerst ) was licensed in
US by US FDA on February 2000, and also is in market in Switzerland,
Argentina and Peru. It is expected to be licensed in Canada early
in 2001. It includes seven purified capsular polysaccharides of
S. pneumoniae, each coupled with a nontoxic variant of diphtheria
toxin, CRM197 (CRM, cross-reactive material). The vaccine contains
capsular polysaccharides from serotypes 4, 9V, 14, 19F, and 23F,
and oligosaccharide from 18C, 6B, the carrier protein CRM 197,
and aluminum phosphate adjuvant. Prevnar contains no thimerosal
or other preservative. Serotypes included in PCV7 accounted for
86% of bacteremia, 83% of meningitis, and 65% of AOM
among children aged <6 years occurring in the United States
during the period 1978-1994.
In a prospective double-blind study among patients
of a health maintenance organization in northern California, a
total of 37,830 healthy children were randomly assigned to receive
either PCV7 or a control (meningococcal C conjugate) vaccine.
Vaccinations were administered at ages 2, 4, 6 and 12-15 months
concurrently with routine licensed vaccines. When all cases of
invasive disease were evaluated during follow-up analysis in April
1999, PCV7 was 97.4% efficacious against vaccine serotypes among
children who were fully or partially vaccinated respectively.
No increase in invasive disease due to by nonvaccine serotypes
Among children who received >1 doses
of study vaccine, use of PCV7 resulted in 11.4% fewer episodes
of clinical pneumonia. Cases of clinical pneumonia accompanied
by an X-ray with any evidence of an infiltrate were reduced by
33.0%. among children who had clinically diagnosed pneumonia and
X-ray evidence of an area of consolidation of >2.5
cm as read by both a pediatrician and a radiologist, efficacy
of PCV7 was 73.1%.
Compared with who received control vaccine, children
who received PCV7 had 6.4% fewer episodes of AOM, and they underwent
20.3 % fewer tympanostomy tube placements.
The ability of PCV7 to protect children against
AOM was also evaluated in an efficacy trial conducted in Finland.
In this trial the estimated efficacy was found to be 57% against
culture-confirmed AOM caused by vaccine serotypes. (8)
Prevention of pneumococcal infections among young
children after widespread use of PCV7 might result in decreased
use of antibiotics, as reported in the Northern California Kaiser
Permanente vaccine efficacy trial . A reduction in antibiotic
use might slow or reverse the trend of increasing prevalence of
antimicrobial resistance among pneumococci.
Duration of Protection
Duration of protection after vaccination with
PCV7 is unknown. However, immunologic memory does occur. Among
infants aged <20 months who received primary vaccination
with two or three doses of PCv7, administration of PPV23 (Pneumococcal
polysaccharide vaccine 23) <18 months later resulted
in a booster response. A similar response was elicited among children
aged 2-3 years when administered PPV23 <20 months after
a bivalent CRm197 conjugate vaccine. Additional studies of PCV7
with longer follow-up periods are needed. Evaluation of duration
of protection will be critical for older children at high risk
for disease (e.g. those with SCD or HIV infection).
Recommendation for Use of PCV7
All children aged <23 months should
be vaccinated with PCV7. Infant vaccination provides the earliest
possible protection, and children aged <23 months have
the highest rates of pneumococcal infection. PCV7 is safe and
highly efficacious in preventing invasive disease, and it is effective
in preventing a portion of AOM cases and pneumonia among healthy
infants and young children. Children aged 24-59 months should
receive PCV7 vaccination if they are at high risk for pneumococcal
infection caused by an underlying medical condition. This recommendation
applies to the following groups:
- Children with sickle cell disease, and other sickle
cell hemoglobinopathies, or children who are functionally or
- Children with HIV infection
- Children who have chronic disease, including chronic
cardiac and pulmonary disease (excluding asthma), diabetes mellitus,
or CSF leak
- Children with immmunocompromising conditions, including
a)malignancies (e.g. leukemia, lymphoma, Hodgkin's disease);
b) chronic renal failure or nephrotic syndrome; c) those children
receiving immunosuppressive chemotherapy, including long-term
systemic corticosteroids; and d) those children who have received
a solid organ transplant.
The recommended primary series is three doses
given at 2, 4, and 6 months of age with 2 months between doses.
A fourth (booster) dose is recommended at 12 to 15 months of age
or at least 60 days after completion of the primary series. The
proposed vaccination schedule is the same for all children aged
<23 months, regardless of the presence of underlying
medical conditions. Interruption of the vaccination schedule does
not require reinstitution of the entire series or the addition
of extra doses.
For children aged 24-59 months with underlying
medical conditions it is recommended to give 2 doses of PCV7,
administered 2 months apart, followed by one dose of PPV23 administered
>2 months after the second dose of PCV7.
The vaccination can be delayed for children with
moderate or severe illness until the child has recovered, although
minor illnesses (e.g. mild upper-respiratory infection with or
without low-grade fever) are not contraindications to vaccination.
The vaccine should not be given to infants or children with thrombocytopenia
or any coagulation disorder that would contraindicate intramuscular
Dosage and Administration
The dose is 0.5 ml and should be given intramuscularly.
PCV7 can be administered at the same time as other routine childhood
vaccinations in a separate syringe at a separate injection site.
Manufacturers are, currently evaluating the combination of PCV7
with other vaccines in one product.
The PCV7 vaccine has been associated with an
acceptable incidence of adverse effects when given at 2, 4, 6
, and 12 to 15 months of age with concurrent administration of
recommended, age-appropriate vaccines(DtaP, HbOC, DTP, Hepatitis
B, OPV, IPV, MMR). Available data, mostly from NCKP efficacy trial,
suggest that PCV7 may prove to be among the most reactogenic (e.g.,
local reactions and incidence of fever) vaccine of those currently
used. Local reaction like redness, swelling and tenderness occurred
after fourth dose of the vaccine respectively in 10.9%, 12.1%,
and 23.3% of children. Such local reactions are usually self-limited
and require no therapy.
The incidence of fever (body temperature >38
°C within 48 hours of vaccination) occurred in 21% of children
vaccinated with PCV7 compared with 17% of children of the control
vaccine group. Of 727 children who received PCV7 without any concurrent
vaccine 45.8 % experienced irritability, 15.9% drowsiness, 21.2%
restless sleep, 18.3% decreased appetite, 18.3% vomiting, 6.3%
12.8% diarrhea, and rush or hives 1.2%. Febrile seizures were
more common in the PCV7 group than in controls( 7:1, P=0.039).
Conclusions and Future Areas for Research
Pneumococcal conjugate vaccine Prevnar
is a significant new contribution to the potential control of
pneumococcal disease in young children.. It is the first vaccine
to help prevent pneumococcal diseases such as meningitis, bacteremia,
pneumonia and otitis media, and also to help reduce the resistance
to the antibiotics traditionally used to treat these infections
in children <2 years of age.
With licensure and introduction of PCV7, close
monitoring of disease trends and long-term vaccine safety will
be high priorities for public health organizations and health-care
providers. Postlicensure surveillance will be necessary to a)
detect potential changes in serotype distribution, including any
increase in disease caused by serotypes not contained in PCV7;
b) follow trends in antimicrobial resistance ant antibiotic use;
c) detect potential herd immunity induced by widespread use of
PCV7; d) track vaccine related health events.
The following ongoing studies are necessary to
determine the most effective use of PCV7: optimal vaccination
schedule for older children at high risk; combined vaccines including
PCv7 and other routine vaccines for infants to reduce the number
of required separate injections; studies of safety, immunogenicity,
and efficacy among adults at high risk for pneumococcal infection;
duration of infection; identifying and defining immune system
correlates of protection and development of alternative pneumococcal
For More Information:
Preventing Pneumococcal Disease Among Infants and Young Children
Recommendations of the Advisory Committee on Immunization Practices
MMRW October 06,2000/49 (RR09);1-38
Technical Report: Prevention of Pneumococcal Infections, Including
the use of Pneumococcal Conjugate and Polysaccharide Vaccines
and Antibiotic Prophylaxis
Gary D. Overturf, MD and the Committee on Infectious Diseases
Vol 106 No.2 August 2000, pp. 367-376
Policy Statement: Recommendations for the Prevention of Pneumococcal
Infections, Including the Use of Pneumococcal Conjugate Vaccine
(Prevnar), Pneumococcal Polysaccharide Vaccine, and Antibiotic
Committee on Infectious Diseases
Vol 106, No. 2 August 2000, pp. 362-366
- Efficacy of Heptavalent
Conjugate Pneumococcal Vaccine (Lederle Laboratories) in 37,000
Infants and Children. Results of the Northern California Kaiser
Permanente Efficacy Trial.
Black S, Shinefield H, Ray P, et al.
Pediatric Infectious Disease
Journal,Vol 19: March 2000; 187-95
- Projected Cost-effectiveness
of Pneumococcal Conjugate Vaccination of Healthy Infants and
Tracy A. Lieu, G. Thomas Ray, Steven B. Black, Jay C. Butler,
Jerome O. Klein, Robert F. Breiman, Mark A. Miller, Henry R.
March 15, 2000- Vol 283, N0.11; 1460-8
Health Canada grants Priority Review to Prevnar™
- Trends in Antimicrobial
Resistance in Streptococcus pneumoniae in Children During a
Period of Changing Antimicrobial Use in Toronto, Canada
J. D. Kellner, D. E. Low, A. Schuchat, E. Mahalingham, Barbara
M. Willey, L.M. Landry, E. Goldenberg, A. J. McGeer.
39th ICAAC, September 1999, San Francisco, (Poster
Second International Symposium on Pneumococcal Diseases,
March 2000, Sun City, South Africa (Poster presentation P86)
- Effect of heptavalent pneumococcal
conjugate vaccine (PNCCRM) on pneumococcal acute otitis media
(AOM) by serotype [Abstract 020].
Kilpi T, Jokinen J, Herra E, et al.
2nd International Symposium
on Pneumococci and Pneumococcal Diseases,
Sun City, South Africa, 2000.