Pneumococcal Polysaccharide Vaccine
Pneumococcal polysaccharide vaccine is used for active
immunisation against Strep.
pneumoniae which is the most common cause of bacterial pneumonia
worldwide. The
currently available pneumococcal vaccine, includes 23 purified
capsular polysaccharide
antigens of S. pneumoniae (Serntypes 1, 2, 3, 4, 5, 6B, 7F, 8,
9N, 9V, 10A, 11A, 12F, 14,
15B, 17P, 18C, 19A, 19F, 20, 22F, 23F, 33F). The vaccine covers
serotypes responsible
for at least 85% of pneumococcal infections and has a >90%
coverage against serotypes
that are penicillin resistant. The immunity is acquired from the
1 'h-l 5h day after the
injection. Pneumococcal capsular polysaccharide antigens induce
type-specific antibod-
ies that enhance opsonization, phagocytosis, and killing of
pneumococci by leukocytes
and other phagocytic cells. After vaccination, an antigen-
specific antibody response,
indicated by a two fold or greater rise in serotype-specific
antibody, develops within 2-3
weeks in more or equal to 80% of healthy young adults; however,
immune responses may
not be consistent among all 23 serotypes in the vaccine.
Adverse Effects : Possible reaction of hypersensitivity.
Sometimes; Redness, slight pain
and induration at the site of injection, associated in some rare
cases with a moderate fever
during about 24 hours (average time). When revaccination is
performed too early, more
important local reactions may occur.
Special Precautions : The safety of pneumococcal polysaccharide
vaccine during the
first trimester of pregnancy has not been evaluated, although no
adverse consequences
have been reported among new-borns whose mothers were
inadvertently vaccinated
during pregnancy.
Contraindications : Safety during first trimester of pregnancy
has not been established.
Indications : Prevention of pneumococcal infections, particularly
those of respiratory
origin in all subjects over the age of 2 years who are at risk of
serious pneumococcal
infection.
Dosage : S.C. orl.M. route: First vaccination: A single injection
confirs protection against
pneumococcal types contained in the vaccine. Revaccination :
Should not be carried before at least 5 years, unless the subject
is particularly exposed.
Polysaccharide Pneumococcal Vaccine Development
Early attempts at immunisation against 5. pneumoniae occurred before the importance of type-specific immunity was understood.
The first available vaccination against specific serotypes was a hexavalent vaccine but it was soon withdrawn from the market. Penicillin had been introduced into clinical use just in time to prevent tens of thousands of deaths from infected battlefield wounds in World War ll (42) and there was little interest in a vaccine against a disease which could be easily treated with the new wonder drug.
Interest in prevention and vaccination was revived when it became clear that there was continued mortality due to pneumococcal infection despite the use of antibiotics. A vaccine against 14 serotypes was licensed in 1977 followed by 23-valent polysaccharide vaccines, including PNEUMO 23 in 1983.
Official Recommendations
Vaccination is recognised worldwide as an effective strategy for preventing invasive pneumococcal infections (1). Groups at risk of infection include adults 65 years of age or older, anyone over 2 years of age who has a long-term health problem, anyone over 2 years of age who has a. disease or condition that lowers the body's resistance to infection, anyone over 2 years of age who is taking any drug or treatment that lowers the body's resistance to infection and Alaskan Natives and certain Native American populations.
The specific recommendations of the U.S. Department of Health and Human Services' Advisory Committee on Immunization Practices (ACIP) are shown in Table 5-2. They are representative of most national recommendations.
Table 5-2: Advisory Committee on Immunization Practices (ACIP) Recommendations for the use of Pneumococcal Vaccine
Groups for which vaccination Strength of Revacci nation7
is recommended recommendation*
Immunocompetent persons(iii) A Second dose of vaccine if patient
Persons aged >65 years received vaccine >5 years previously
and were aged <65 years at the time of vaccination.
Persons aged 2-64 years with A Not recommended.
chronic cardiovascular disease,(iv)
chronic pulmonary disease,(v) or
diabetes mellitus
Persons aged 2-64 years with B Not recommended.
alcoholism, chronic liver disease,(vi)
or cerebrospinal fluid leaks
Persons aged 2-64 years with A If patient is aged >10 years: single
functional or anatomic asplenia(vii) revaccination >5 years after previous
dose. If patient is aged <10 years:
consider revaccination 3 years after previous dose.
Persons aged 2-64 years living in C Not recommended.
special environments or social
settings (viii)
Immunocompromised persons(iii) C Single revaccination if >5 years have
Immunocompromised persons elapsed since receipt of first dose. If
aged >2 years, including those patient is aged <10 years: consider
with HIV infection, leukemia, revaccination 3 years after previous
lymphoma, Hodgkins disease, dose.
multiple myeloma, generalized
malignancy, chronic renal failure,
or nephrotic syndrome; those rec-
eiving immu-nosuppres-sive chem-
otherapy (including corticos-teroids);
and those who have received an
organ or bone marrow transplant.
(i) The following categories reflect the strength of evidence supporting the recommendations for vaccination:
A=Strong epidemiologic evidence and substantial clinical benefit support the recommendation for vaccine use.
B=Moderate evidence supports the recommendation for vaccine use.
C=Effectiveness of vaccination is not proven, but the high risk for disease and the potential benefits and safety of the vaccine justify vaccination.
(ii) Strength of evidence for all revaccination recommendations is "C."
(iii) lf earlier vaccination status is unknown, patients in this group should be administered pneumococcal vaccine.
(iv) Including congestive heart failure and cardiomyopathies.
(v) Including chronic obstructive pulmonary disease and emphysema
(vi) lncluding cirrhosis.
(vii) lncluding sickle cell disease and splenectomy.
(vii)Including Alaskan Natives and certain American Indian populations.
CDC, MMWR 1997'81
Health authorities in Australia, Mexico, Argentina, Brazil, Indonesia, Malaysia, and South Africa, amongst others, recognise the effectiveness of pneumococcal vaccination and recommend vaccination for the elderly and other at-risk groups described above. These recommendations are also recognised by the WHO, American health organisations (e.g. ACIP) and the majority of European countries.
More and more national health bodies are recommending pneumococcal polysaccharide vaccinations in the elderly and other at-risk groups. Many countries recognise the cost-effectiveness of vaccination and reimburse the costs. The current national recommendations in some countries in 2005 are shown in Table 5-3.
Recommendations are expected to be introduced in Peru 2005-2006 for people in at-risk groups and may be recommended for the elderly as part of the public immunisation plans in both Colombia and Chile in 2006-2007.
Table 5 - 3 : National Recommendations for Pneumococcal Vaccination in 2005
Country Recommendations
Argentina Elderly>65 People at risk
Australia Elderly >65 People at risk
Brazil Existing: people at risk AND >65
Expected: extension to elderly >60 and to people at risk
Germany Elderly >60 People at risk
Indonesia Elderly>55 People at risk (Beginning in 2005)
Malaysia Existing: Elderly>65, people at risk Expected: Pilgrims to Mecca
Mexico Elderly >60 People at risk
South Africa Chronic disease, splenectomy, immunocompromised individuals,
Elderly >65 years
Turkey Elderly >65 People at risk
USA Elderly >65 People at risk
Immunogenicity
Pneumococcal capsular polysaccharide antigens induce type-specific antibodies that enhance opsonisation, phagocytosis, and killing of S. pneumoniae by leukocytes and other phagocytic cells.
In humans, the capsular polysaccharide vaccine, after intramuscular (i.m.) injection, induces IgG and IgM antibody type.
After vaccination, an antigen-specific antibody response, indicated by a twofold or greater rise in serotype-specific antibody, develops within 2-3 weeks in >80% of healthy young adults'8'; however, immune responses may not be consistent among all 23 serotypes in the vaccine'431. The levels of antibodies that correlate with protection against pneumococcal disease have not been clearly defined.
Although the duration of protection has not yet been determined it may last approximately 5 to 10 years. Encouraging and concordant studies from a randomized controlled trial in France, from 3 of 4 case-control studies, and from the epidemiological analysis by the CDC, all support the consensus that pneumococcal polyvalent vaccines are effective in immunocompetent older persons with high-risk conditions.
Antibody responses also occur in the elderly and in patients who have alcoholic cirrhosis, COPD, and insulin-dependent diabetes mellitus<7); however, antibody concentrations and responses to individual antigens may be lower among such persons than among healthy young adults<43>.
Persons aged 2 years or more with anatomic or functional asplenia generally respond to pneumococcal vaccination with antibody levels comparable with those observed in healthy persons of the same age<44).
Clinical Efficacy and Effectiveness
Antibody response to invasive pneumococcal serotypes has been shown to occur in healthy adults as well as in the elderly and at-risk groups. Several clinical trials have been conducted evaluating the efficacy of vaccine against pneumonia and pneumococcal bacteraemia. In addition, multiple case-control and serotype prevalence studies have provided evidence for pneumococcal vaccine effectiveness against invasive disease.
The efficacy of pneumococcal polysaccharide vaccines was first established in randomised controlled trials of a 14-valent among novice gold miners in South Africa in the 1970s(45).
Retrospective studies have shown that pneumococcal vaccination is approximately 50-80% effective in preventing invasive pneumococcal disease'46'. Effectiveness of pneumococcal vaccination against invasive disease caused by vaccine serotypes in immunocompetent patients was studied in 11 hospitals in the USA according to age and time since vaccination (Connecticut, USA, 1984-1990)'47'. Aggregate effectiveness against vaccine-serotype invasive disease in immunocompetent persons was 61%(47).
Table 5 - 4: Effectiveness of pneumococcal Vaccination against invasive disease
Age group(years) No of case-control pairs Time since vaccination
<3 years 3-5 years
18-54 125 89 (74,96)* 85 (62,94)
56-64 149 82 (57,93) 75 (38,90)
65-74 213 71 (30,88) 58 (-2,83)
75-84 188 53 (-15,81) 32 (-67,72)
>85 133 22 (-90,68) -13 (-174,54)
Shapira et al, 1991(47) *95% confidence interval
In an indirect cohort study(48), S. pneumoniae was isolated from CSF or blood from 2837 patients in the US between 1978 and 1992. Vaccine effectiveness in patients with underlying illness was estimated by comparing the proportion of pneumococcal infections in vaccinated and unvaccinat-ed groups.
The results are summarised in Figure 5-1. It should be noted that the data are for patients who received 14-valent or 23-valent vaccine. Overall effectiveness for patients receiving 23-valent vaccine was 60%.
A retrospective case-controlled study<49> showed that vaccination significantly decreased the risk of pneumonia and decreased the risk of death from any cause and death from pneumonia.
Cost Effectiveness
Given the impact in terms of treatment, hospitalisation and long term care costs resulting from pneumococcal disease, vaccination might be expected to have economic as well as health benefits. Recent studies have shown the pharmoeconomic benefits of vaccination in certain circumstances. Vaccination of elderly people against bacteraemia is one of the few interventions that have been found to both improve health and save medical costs(50).
The cost-effectiveness of pneumococcal vaccination varies across countries and the disease examined. A study of five western European countries(51> showed pneumococcal vaccination "acceptably to moderately cost-effective and even cost-saving". On the basis of the findings of this study, they recommended public health authorities to consider policies for encouraging pneumococcal vaccination of all persons aged over 65.
A cost-effective ness study in Spain showed that for people aged over 45 years, pneumococcal vaccination is cost-effective (45-64 years), and can be cost-saving in certain cases (over 65 years)(52). They conclude that pneumococcal vaccination is a wise investment.
An American Advisory Committee on Immunization Practices (ACIP) study showed that vaccination generated health benefits among high-risk people and could even be cost-saving when future medical costs of survivors are not taken into account(53). The same study found vaccination "a wise investment for non high risk people". Their findings could also support the consideration of extending recommendation for vaccination of people aged 50 to 64 years(53).
Strategies and Opportunities
The delivery and acceptance of recommended vaccinations is an ongoing challenge for health-care providers and public health systems, but specific interventions can increase levels of vaccination coverage(54). Some opportunities for penumococcal vaccination are shown in table 5-5.
Table 5-5 : Opportunities for pneumococcal vaccination
Who? When?
Age > 65 years Regular return visits to general practitioner or
and/ or persons at risk hospital concomitantly with influenza (see sect-
ion 5.8) dishcharge form hospital
residency in nursing home or other chornic care
facility
Persons undergoning spl- 2 weeks before elective surgery, organ transpl-
enectomy or chemotherapy antation cancer chemotherapy, immunosuppres-
sive treatment
Persons with HIV infection On diagnosis of HIV seropositivity
Client reminder/ recall systems, education of target populations, provider reminder/ recall systems including in-hospital, pre-discharge reminders, medical record reminders and computer-based reminders, and standing orders have been shown to be effective in increasing vaccination rates'54' and are strongly recommended by the Centers for Disease Control and Prevention (CDC) of the US Department of Health.
Pneumococcal Vaccines: a missed opportunity?
With the advent of penicillin and other effective anti-pneumococcal drugs, interest in prevention of pneumococcal disease waned(55>. However, S. pneumoniae remain an important cause of disease and hospitalisation and vaccination is recognised by international and national health bodies (section 5.2) as an important public health measure. Despite these recommendations, vaccination rates in target groups are often below target figures(56).
Why are adult immunisation rates so low?
A number of reasons have been suggested by the United States National Vaccine Advisory Committee for low adult immunisation rates. They include misperceptions about the risks of vaccine-preventable diseases in adults, vaccine safety and efficacy, the size of the target population, the lack of regulatory and/or legal requirements, reimbursement and the lack of coordinated adult immunisation programs(56).
In a 1996 survey of primary care physicians in Massachusetts, 24% of respondents identified oversight as the most important barrier to reducing the number of patients they immunize; more than any other financial, administrative or clinical consideration (57). Although patient's opinion is an important determinant of vaccination coverage in adults, lack of physician's encouragement accounted for most missed vaccination opportunities in one study in Switzerland(58).
Hospitalization frequently represents a missed opportunity for vaccination. One US study observed that up to 80% of hospitalized adults age over 65 years did not receive or were not noted to have had pneumococcal vaccination during hospitalization(59) despite the recommendations for use in this group(8) and the eligibility for free vaccination since Medicare has paid for pneumococcal vaccination since 1981(59).
Pneumococcal and Influenza Vaccines
Of special interest is simultaneous administration of a polysaccharide pneumococcal vaccine with an influenza vaccine such as Vaxigrip. The indications are similar18' so there is a high degree of overlap between target groups and no contraindications against simultaneous administration.
Concurrent administration of these vaccines is safe and not associated with increased rates of side effects, so health-care providers should take advantage to ensure that people at-risk are immunized with both of these vaccines.
Elderly people recognise the importance of yearly vaccination against influenza and are prepared to make the effort to get vaccinated. These yearly visits can give the physician the opportunity to discuss the benefits of pneumococcal vaccination.
Additive health benefits can be achieved at a population level through the use of both vaccinations, preventing the complications of hospitalisation and death associated with these diseases(60). Additive preventative effects have been noted in dual-vaccinated elderly persons with a reduction of hospital admissions for influenza (37%), pneumonia (29%) and invasive pneumococcal disease (44%) as well as lower mortality due to pneumonia, chronic obstructive pulmonary disease and cardiac failure(61).
A large scale study showed that influenza and pneumococcal vaccination in the elderly over 65 years of age lead to a 30%-52% reduction in hospital admission and 57% reduction in mortality(62).
Another study demonstrated that, for elderly persons with chronic lung disease, influenza and pneumococcal vaccinations have additive health benefits to offer these high-risk persons during influenza seasons with fewer hospitalisations for pneumonia and fewer deaths(63).
Dual-vaccination can also be cost-saving(63). A further analysis demonstrated that combined vaccination was a reasonably cost-effective preventive alternative against pneumococcal infections, and also that the cost-effectiveness ratio could be reduced by targeting the intervention or lowering the cost of the intervention(64).
It must be stressed that, unlike influenza vaccination, pneumococcal vaccination should not be given annually. One dose is usually sufficient although revaccination is recommended in some cases.
Composition and Presentation
PNEUMO 23β’ is a clear colourless solution for injection by intramuscular (i.m.) or subcutaneous (s.c.) route. Each single dose syringe (O.SmL) contains 25 micrograms of Streptococcus pneumoni-ae purified polysaccharides of each of the following 23 types:
1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F.
Each O.5 mL dose also contains phenol <1.25mg as a preservative in a phenol buffered solution of sodium chloride, disodium phosphate, monosodium phosphate and water for injections. The vaccine should be used d irectly as supplied; no dilution or reconstitution is necessary.
The 23 serotypes cover approximately 85-90% of the serotypes isolated in invasive pneumococcal infections (8). Owing to the increased number of serotypes included in this vaccine compared to the previously available 14-valent vaccines, the amount of each capsular polysaccharide antigen has been reduced from 50ug/ dose to 25ug/dose compared with the previous 14-valent vaccine(65). This has helped to reduce local reactions caused by the total amount of administered polysaccharide without significantly reducing the serological response to the individual antigens(65).
The serotypes included in PNEUMO 23β’ also include the most antibiotic resistant strains including 88% of penicillin resistant strains.
Immunogenicity
For a vaccine to work it must induce an immune response. Pneumococcal capsular polysaccharide antigens induce type-specific antibodies that enhance opsonisation, phagocytosis, and killing of pneumococci by leukocytes and other phagocycotic cells. Immunogenicity is measured as the increase in specific antibody levels in the serum.
PNEUMO 23β’ has been licensed since 1987. As with all vaccines it has undergone extensive studies to establish its immunogenicity. Administration of PNEUMO 23β’ has been shown to result in the production of type-specific antibodies in healthy adults (66). The levels of pneumococcal capsular polysaccharide antibodies which correlate to protection against pneumococcal disease have not been clearly defined (8) but a two-fold increase or greater rise in serospecific antibody response is seen in 80% or more of healthy young adults.
In three open uncontrolled studies carried out in France in the 1980's on healthy adults (66) the pneumococcal antibody titres to each of the 23 serotypes included in PNEUMO 23β’ were measured by radioimmunoassay methods.
In the first clinical trial conducted in 1984, the geometric mean post-vaccination antibody titres were 5.75 higher than before vaccination titres. At least 80% of subjects had a two-fold or greater increase in antibody levels. A post-vaccination titre equal to or greater than BOOng antibody nitrogen/ml was achieved in over 80% of subjects.
In clinical studies involving more than 1,000 volunteers, serum capsular polysaccharide antibodies start to increase 10 to 15 days following immunisation with the pneumococcal polysaccharide vaccine.
Elderly
The elderly often have a naturally decreased immune system. Since they are a group which can benefit from protection it is important to show that vaccination is effective in this population.
34 persons aged from 65 to 94 years old were included in the first clinical trial (66). The overall geometric mean antibody levels to the 23 serotypes in both age groups were identical. Both showed on average at least a four-fold increase although there were differences in the response to individual serotypes. Almost 90% of elderly people achieve antibody levels 300ng antibody nitrogen/mL.
Another study assessed the antibody response to PNEUMO 23β’ in 350 elderly subjects (67). Specific IgG antibodies to pneumococcal serotypes 4, 6B, 9V, 14, 19F and 23F were measured. Vaccination significantly increased the geometric mean concentration of antibodies to all six serotypes in all three age groups studied. There was some decrease with increasing age but it was not statistically significant.
PNEUMO 23β’ is as effective in most elderly people as it is in younger adults.
With Flu Vaccine
An open, randomised clinical trial was conducted in Italy to assess the immunogenicity of pneumococcal and influenza vaccine (VAXIGRIP) administered simultaneously(68).
Immunisation significantly increased influenza antibody titres and the percentage of subjects considered to be protected in those that received VAXIGRIP. The groups receiving PNEUMO 23β’ saw a mean increase in post-vaccination antibody levels between 8.8 (PNEUMO 23β’ + VAXIGRIP) and 16.4 (PNEUMO 23β’ only). 73.3% of subjects receiving PNEUMO 23β’ and 67.5% of subjects receiving both vaccinations developed a threefold increase in antibody levels. No clinically important side effects were reported in any group.
Another large scale study(69) assessed adverse effects following simultaneous vaccination of elderly persons with PNEUMO 23β’ and VAXIGRIP The results indicated that PNEUMO 23β’ vaccine administered to elderly subjects either alone or simultaneously with influenza vaccine is both immunogenic and well tolerated.
At-Risk Children
A multi-centre clinical trial was conducted in France to determine the safety and immunogenicity of primary vaccination or revaccination with PNEUMO 23β’ in high-risk children less than 15 years old (66). The study looked at children who had sickle cell disease or had undergone a splenectomy for non-malignant haematological disease.
A good antibody response with a mean fold increase in the GMT always >2 was shown along with an absence of serious side-effects following pneumococcal vaccination in young, at-risk children.
Safety and Tolerance
The safety and tolerance are examined in clinical trials. Following vaccination with PNEUMO 23β’ local reactions at the injection site: pain, erythema, induration and oedema are the more commonly reported reactions. These reactions are generally mild and transient.
Very rare Arthus-like reactions have been reported. They are reversible without after-effects and mainly occur in persons with high initial pneumococcal antibody levels.
Systemic reactions: a moderate and transient fever (>38Β°C) is observed in about 2% of patients. Fever (> 39Β°C) may rarely be observed. Febrile episodes mostly occur very early after vaccination. They are self-resolving within 24 hours.
Other general reactions such as lymphadenopathy, rash, urticaria, arthralgia, anaphylactoid reactions, headache, myalgia, malaise, asthenia and fatigue have been exceptionally reported.
Revaccination
According to the manufacturer's recommendations, given the current state of knowledge, there is no strong reason to revaccinate people who have previously received pneumococcal vaccine(70). Revaccination is indicated only for patients at particularly high risk of severe pneumococcal infection (patients with a condition which compromises their immune response, and people with splenectomy) and only once: once 3 years later in children under 10 years old and once 5 years later in patients over 10 years old.
Revaccination has been shown to result in increased adverse local reactions but their incidence remains low. Patients with uncertain vaccination status should be offered vaccination. The benefits of vaccination outweigh the possible hazards of accidental revaccination. Revaccination in patients older than 65 years without underlying conditions is not indicated, unless national recommendations exist.
Indications
PNEUMO 23β’ is indicated for high-risk subjects > 2 years of age to prevent pneumococcal pneumonia and systemic pneumococcal infections caused by the serotypes included in the vaccine. Groups who can benefit from PNEUMO 23β’ vaccination are shown in Table 6-1.
Table 6-1: Indications for PNEUMO 23β’ vaccination
At-risk subjects over 2 years of age :
Elderly people from 65 years of age Especially elderly living in institutions
Immunocompetent patients with chronic illness Patients weakened or likely to be frequently hospitalised (diabetes mellitus, chronic bronchitis, respiratory insufficiency, cardiac insufficiency, heavy smokers and drinkers)
Immunocompromised patients Anatomic or functional asplenia (including patients to be splenectomised), sickle cell disease, Hodgkin's disease, lymphoma, multiple myeloma, chronic renal failure, nephrotic syndrome and organ transplantation.
HIV infected patients Special groups Asymptomatic or symptomatic
People living in a social or working environment with an identified increased risk of pneumococcal infection.
NOTE: indications vary in different countries. Check with national recommendations.
PNEUMO 23β’ vaccination is not recommended for children under 2 years of age because antibody responses may be poor in this age group. Also, the safety and efficacy of pneumococcal vaccines have not been established in children less than 2 years of age. It should be noted that recurrent upper respiratory tract infections, particularly otitis media and sinusitis, are not an indication for this vaccination.
Administration
Primary immunisation consists of a single 0.5ml dose. Intramuscular administration is preferred, although subcutaneous injection can be used.
Contraindications
PNEUMO 23β’ should not be administered in the following conditions:
Β· Hypersensitivity to any component of the vaccine.
Β· Usual contraindications to any immunisation: immunisation should be delayed in case of significant febrile illness, acute disease, relapse of chronic disease, unless a lethal risk exists.
Β· Immunisation is not recommended in subjects who were given a pneumococcal vaccine within the previous three years, except in specific indications.
Β· A confirmed or suspected episode of pneumococcal infection is not a contraindication and should be considered according to underlying risk status.
PNEUMO 23β’ Manufacturing Process
PNEUMO 23β’ is a polyvalent pneumococcal vaccine. It contains a mixture of highly purified capsular polysaccharides from each of the 23 serotypes present in the vaccine which are extracted from lyophilised cultures of S. pneumonias.
The extraction and purification conditions are adapted to maintain the integrity and specificity of each polysaccharide. Controls at each stage of production guarantee the identity and quality of the capsular polysaccharides in the final product.