Giuseppe
Emeritus
[Source: World Health Organization, full PDF document: (LINK). Edited.]
Weekly epidemiological record / Relev? ?pid?miologique hebdomadaire
6 april 2012, 87th year / 6 avril 2012, 87e ann?e - No. 14, 2012, 87, 129?144 - http://www.who.int/wer
Pneumococcal vaccines - WHO position paper ? 2012
In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with the current WHO position on the use of vaccines worldwide.
The papers have been reviewed by external experts and WHO staff, and are reviewed and endorsed by the WHO Strategic Advisory Group of Experts on Immunization (SAGE) (http://www.who.int/immunization/sage/en/ ). The position papers are designed to be used mainly by national public health officials and managers of immunization programmes. They may also be of interest to international funding agencies, vaccine manufacturers, the medical community, the scientific media and the public.
The current document replaces the 2007 position paper on 7-valent pneumococcal conjugate vaccine. Incorporating the most recent developments in the field of pneumococcal vaccines this position paper focuses on the currently available 10-valent and 13-valent conjugate vaccines and their introduction and use in national immunization programmes. It also deals with the 23-valent polysaccharide vaccine, though in less detail than provided in the April 2008 position paper which remains valid.
Recommendations on the use of pneumococcal vaccines were discussed by SAGE at its meetings in November 2006 (conjugate vaccine) and April 2008 (polysaccharide vaccine) and most recently in November 2011. Evidence presented at these meetings can be accessed at http://www.who.int/immunization/sage/previous/en/index.html .
Epidemiology
Pneumococcal infections include serious diseases such as meningitis, bacteraemia, and pneumonia, as well as milder but more common illnesses, such as sinusitis and otitis media. The causative agent, Streptococcus pneumoniae, frequently colonizes the human nasopharynx, and is transmitted mainly through respiratory droplets. Infants and young children are thought to be the main reservoir of this agent with cross-sectional point prevalences of nasopharyngeal carriage ranging from 27% in developed to 85% in developing countries.
S. pneumoniae includes >90 serotypes. The distribution of serotypes that cause disease varies by age, disease syndrome, disease severity, geographic region, and over time. Prior to introduction of pneumococcal conjugate vaccines, 6?11 serotypes accounted for ≥70% of all invasive pneumococcal disease (IPD) occurring in children worldwide.(1) IPD is commonly defined as morbidity associated with the isolation of pneumococci from a normally sterile body site, such as the blood stream, or those secondary to blood stream spread, e.g. meningitis or septic arthritis; it does not include sites such as the middle ear which are infected by contiguous spread from the nasopharynx.
Most illnesses are sporadic. Outbreaks of pneumococcal disease are uncommon, but may occur in closed populations, such as nursing homes, childcare centres, or other institutions. However, large outbreaks of meningitis caused by serotype 1 have been reported from the African meningitis belt.(2)
Of the estimated 8.8 million global annual deaths amongst children <5 years of age in 2008, WHO estimated that 476 000 (333 000?529 000) were caused by pneumococcal infections.(3) Disease rates and mortality are higher in developing than in industrialized settings, with the majority of deaths occurring in Africa and Asia. Children with HIV infection are at substantially increased risk of serious pneumococcal disease.(4, 5)
Before widespread immunization with 7-valent pneumococcal conjugate vaccine, the mean annual incidence of IPD in children aged <2 years was 44.4/100 000 per year in Europe and 167/100 000 in the United States.(6, 7) In comparison, the annual incidence of IPD in children <2 years in Africa ranged from 60/100 000 in South Africa prior to the HIV epidemic to 797/100 000 in Mozambique.(5, 8, 9)
Some of the differences could be explained by differences in case ascertainment and surveillance sensitivity, though incidence in Africa did appear to be generally higher than in Europe or North America.
In Europe and the United States, S. pneumoniae is estimated to cause approximately 30%?50% of community-acquired pneumonia (CAP) requiring hospitalization in adults. In children, pneumococcal species were found in 78% and 13% of the cases respectively, among the 284 cases of lobar pneumonia and the 515 cases of bronchopneumonia proven to be of bacterial etiology by transthoracic needle aspiration.(10) In children <2 years of age a systematic Cochrane review of pneumococcal conjugate vaccines showed a pooled vaccine efficacy of 27% (95% CI, 15%?36%) against all cause pneumonia as defined by a WHO ? consensus case definition.(11)
There is a temporal relation between the incidences of CAP and documented circulation of influenza and respiratory syncytial viruses.(12)
In many countries routine use of pneumococcal conjugate vaccines has dramatically reduced the incidence of IPD and in some places IPD caused by vaccine serotypes has virtually disappeared, even in age groups not primarily targeted by the immunization programme (herd immunity effect).(13)
Pathogen
S. pneumoniae is a Gram-positive, encapsulated diplococcus. The polysaccharide capsule of this bacterium is an essential virulence factor and the >90 distinct pneumococcal serotypes are defined on the basis of differences in the composition of this capsule. In general, immunity following infection is serotype-specific, but cross-protection between related serotypes can occur. While a wide variety of serotypes cause non-invasive diseases such as otitis media and sinusitis, serotypes 1, 5, 6A, 6B, 14, 19F, and 23F are common causes of IPD globally in children <5 years of age. Serotypes 1, 5, and 14 together account for 28%?43% of IPD across regions and for about 30% of IPD in 20 of the world?s poorest countries; serotypes 23F and 19F are responsible for 9%?18% of cases globally. Serotype 18C is common in regions with a large proportion of high-income countries (i.e., Europe, North America, and Oceania).(1) Some serotypes such as 6B, 9V, 14, 19A, 19F, and 23F are more likely than others to be associated with drug resistance.(14)
Laboratory diagnosis of S. pneumoniae based on growth in culture media can be made in most clinical microbiology laboratories, although prior antibiotic treatment, improper handling or transport of specimens, or use of inappropriate culture media, may result in failure to isolate the organism. Some of the observed geographical variation in serotype distribution may be attributable to factors including differences in selection of patients, the frequency and quality of blood-culture, pneumococcal vaccination programmes, and antibiotic policy.(15)
Disease
Pneumococcal infection and disease can affect a variety of organ systems resulting in a number of disease syndromes. Although temporary colonization of the nasopharyngeal mucosa, which is the primary focus of infection, rarely results in disease, certain pneumococcal serotypes may occasionally invade the blood stream causing bacteraemia and possibly infection of secondary sites such as the meninges. In other instances, contiguous spread from the nasopharynx may cause diseases such as otitis media or sinusitis. Pneumonia is often caused by aspiration of pneumococci from the nasophaynx. When associated with bacteraemia, pneumonia is classified as IPD.(16)
Due to its unambiguous microbiological diagnosis, the incidence of IPD is frequently used as a measure of the incidence of severe pneumococcal disease in general. On average, about 75% of IPD cases and 83% of pneumococcal meningitis occur in children aged <2 years, but these incidences vary considerably, as does the distribution of cases in age strata below 2 years. For pneumonia, between 8.7% and 52.4% of cases occur in infants aged <6 months.(16)
Case fatality rates (CFR) can be high for IPD, ranging up to 20% for septicaemia and 50% for meningitis in developing countries. Mortality is greatest in younger infants. Even in industrialized countries, the overall CFR for pneumococcal bacteraemia may reach 15%?20% among adults and 30%?40% among elderly patients, despite appropriate antibiotic therapy and intensive care. Among meningitis survivors, long-term neurological sequelae such as hearing loss, mental retardation, motor abnormalities and seizures have been observed in frequencies as high as 58% of cases.(17) Pneumococcal middle-ear infection and sinusitis are less severe, but they are considerably more common health problems worldwide.
Lack of exclusive breastfeeding, nutritional deficiencies, and indoor air pollution are risk factors for pneumonia, including pneumococcal pneumonia, in infants and young children.(18) Apart from the high incidence in children <2 years of age, the risk for pneumococcal disease is increased in the elderly (>65 years of age), and in people who use tobacco or alcohol excessively. This risk is also increased in individuals who suffer from chronic medical conditions, such as heart disease, lung disease, diabetes, or asplenia, or from other conditions that suppress the immune system, such as advanced HIV infection. Development of pneumococcal resistance to commonly used antibiotics such as penicillins, macrolides, cephalosporins, and co-trimoxazole is a serious problem in some parts of the world. However, following the introduction of large-scale pneumococcal immunization a reduction in the circulation of drug-resistant strains has been observed.(14)
A definitive diagnosis of pneumococcal infection can be made by isolating the bacterium from blood or other normally sterile body sites, such as cerebrospinal fluid, but the etiological diagnosis is problematic in cases of non-bacteraemic pneumococcal pneumonia.
Pneumococcal vaccines
Vaccines have been used to prevent pneumococcal disease for more than 30 years. Currently, there are 2 different types of pneumococcal vaccines on the market:
(1) a 23-valent polysaccharide vaccine (PPV23) available since the early 1980s and
(2) 2 conjugate vaccines available since 2009, one 10-valent (PCV10) the other 13-valent (PCV13).
The 7-valent conjugate vaccine (PCV7) is gradually being removed from the market.
Pneumococcal polysaccharide vaccines are associated with poor or absent immunogenicity in children <2 years of age and failure at any age to induce an anamnestic antibody response upon revaccination. The term pneumococcal conjugate vaccine refers to vaccines based on chemical coupling of S. pneumoniae polysaccharides to an immunogenic protein carrier. This enhances the antibody response and induces immune memory.
23-valent pneumococcal polysaccharide vaccine
PPV23 includes the serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B,17F, 18C, 19A, 19F, 20, 22F, 23F and 33F. For primary immunization, PPV23 is administered as a single intramuscular or subcutaneous dose. Revaccination is not normally recommended in immunologically healthy individuals, but 1 or 2 revaccinations have been practiced in immunocompromised individuals.(13)
In some high- or middle-income countries PPV23 is recommended for populations proven to be at increased risk of morbidity and mortality from pneumococcal infection, including adults aged >65 years. PPV23 is also used to supplement the immune response following primary vaccination with one of the pneumococcal conjugate vaccines (see below). Developing countries have not made the use of PPV23 a priority.
Comprehensive meta-analyses of studies assessing PPV23 vaccine efficacy and effectiveness have been conducted, including a 2007 WHO-commissioned meta-analysis and a review of randomized controlled trials (RCTs).(19, 20) On balance, as shown in the meta-analyses, the results of the RCTs of PPV23 are consistent with a protective effect against IPD and all-cause pneumonia among generally healthy young adults and, to a lesser extent, protection against IPD in the general population of elderly people. Such trials have not demonstrated that PPV23 is efficacious against either IPD or all-cause pneumonia in populations at higher risk, such as adults and children with underlying conditions that increase their risk of pneumococcal disease or highly immunosuppressed individuals of any age.(20)
PPV23 is considered safe both in terms of severe immediate reactions and potential long-term adverse consequences.
Detailed information on the PPV23 is provided in the position paper published in 2008.(21) Key conclusions are also stated in the final WHO position in the current text.
Conjugate vaccines
This position paper focuses on PCV10 and PCV13 and their use in children. Evidence in support of the use of PCVs for immunization of older populations and the potential use of such vaccines for immunization in pregnancy to protect newborn babies is currently not considered sufficient to support policy recommendations, but will be reviewed regularly as part of the process of updating the position papers. PCV10 is composed of the capsular polysaccharides purified from 10 serotypes: 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Each is conjugated to a carrier protein, either protein D (an outer membrane protein from non-typable Haemophilus influenzae), tetanus toxoid, or diphtheria toxoid. Protein D is used as carrier protein for 8 of the 10 serotypes (serotypes 1, 4, 5, 6B, 7F, 9V, 14 and 23F); serotype 19F is conjugated to diphtheria toxoid and serotype 18C is conjugated to tetanus toxoid. PCV10 is adjuvanted with aluminium phosphate, and presented in a single dose syringe or as 1 or 2 dose vial.
Latex is contained within the syringe component. The volume per dose is 0.5ml. Each dose contains 1 μg of polysaccharide for serotypes 1, 5, 6B, 7F, 9V, 14 and 23F, and 3 μg of serotypes 4, 18C and 19F. PCV13 contains polysaccharide antigens of the pneumococcal capsular serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, individually conjugated to a nontoxic diphtheria CRM 197 (CRM, cross-reactive material) carrier protein. A 0.5ml PCV13 dose contains approximately 2 μg of polysaccharide from each of 12 serotypes and approximately 4 μg of polysaccharide from serotype 6B. The vaccine contains aluminium phosphate as adjuvant. PCV13 is available in single dose, pre-filled syringes that do not contain latex and in single dose vials.(22, 23)
Both PCV10 and PCV13 are preservative-free, their recommended storage temperature is 2?8 ?C, and the vaccines must not be frozen.
A systematic review and meta-analysis of IPD serotype data obtained from children <5 years of age during the period 1980?2007, i.e. before national PCV7 introduction, showed that the serotypes included in PCV7 accounted for ≥49% of IPD in each geographic region, although with substantial regional variation (range: 49%?82%), with highest serotype coverage in North America and Europe. The corresponding estimated coverage for serotypes included in PCV10 and PCV13 reached ≥70% of IPD in every region (range: 70%?84% and 74%?88%, respectively).
Indication and administration
Although the exact labelling details may differ by country, both PCV10 and PCV13 are licensed for active immunization for the prevention of invasive disease, pneumonia and acute otitis media caused by the respective vaccine serotypes of S. pneumoniae in infants and children from 6 weeks to 5 years of age. In addition, PCV13 is licensed for the prevention of pneumococcal disease in adults >50 years of age.(22, 23)
PCVs are not indicated for treatment of pneumococcal disease and are unlikely to prevent infection caused by S. pneumoniae serogroups that are not included in the vaccines. The immune responses to the PCV carrier proteins diphtheria cross-reactive protein (PCV13), and tetanus and diphtheria toxoids (PCV10), have not been studied. However, with PCV10, one trial showed a protective effect (35.3%; 95% CI, 1.8-57.4) against otitis media caused by non-typable H. influenzae, possibly attributable to the vaccine?s H. influenzae-derived carrier protein.(24)
The vaccines are given by injection into the anterolateral aspect of the thigh in infants and into the deltoid muscle in older age groups. For PCV10 and PCV13, the manufacturers recommend 3 primary doses with an interval of at least 4 weeks between doses, plus a booster at least 6 months after the third dose (3p+1 schedule). The first can be given as early as 6 weeks of age; the booster dose is given preferably between 11 and 15 months of age. An alternative schedule consists of 2 primary doses given 2 months apart, starting at 2 months of age, followed by a booster at least 6 months after the second dose (2p+1 schedule).
The manufacturers further recommend that previously unvaccinated infants aged 7?11 months should receive 2 doses, the second dose at least 4 weeks after the first, followed by a third dose in the second year of life. For PCV10, unvaccinated children 12 months to 5 years of age should receive 2 doses, with an interval between the first and second dose of at least 2 months. For PCV13, unvaccinated children aged 12?24 months should receive 2 doses, children aged 2?5 years should receive a single dose; adults >50 years of age should receive a single dose.
A variety of off-label schedules have been evaluated, as discussed later in this paper, and some of these are being used in national immunization programmes.
Serological criteria for evaluation of pneumococcal conjugate vaccines
Results of studies on vaccine efficacy or effectiveness against IPD, otitis media, or pneumonia were not available at the time of initial licensure of PCV10 and PCV13. Since non-inferiority trials comparing these vaccines against PCV7, using clinical end-points, would require very large sample sizes and would be prohibitively expensive, licensure both of PCV10 and PCV13 was based on non-inferiority trials using serological end-points. These trials demonstrated similar immunogenicity profiles between the latter vaccines and PCV7 against most of their common serotypes, as well as a favourable immunogenicity profile also for the additional serotypes of PCV10 and PCV13.
For the serotypes common to the new vaccine and the licensed comparator, WHO has defined serological criteria for non-inferiority that should be used in the primary analysis.25 The criteria include (a) the percentage of subjects with serotype-specific IgG ≥0.35 μg/ml using a WHO reference assay (or an alternative and well-justified threshold value based on a specific in-house assay) and (b) the serotype-specific IgG geometric concentration ratios. In addition, in the secondary analysis, it is recommended that comparisons of opsonophagocytic antibody titres of serotypes that are common to the new vaccine and the licensed comparator should focus on serotype-specific geometric mean titres (GMT) ratios rather than the previously used threshold functional titer ≥1:8.
Outcomes of PCV immunization
Two recent systematic reviews(26, 27) have assessed clinical and immunological outcomes of PCV vaccination using data from RCTs and observational studies. Most of the available evidence presented in these reviews pertains to PCV7 or the investigational vaccines PCV9 and PCV11 although available studies on PCV10 and PCV13 were also included.
One review(26) identified 10 RCTs using either 3p+1 or 3p+0 PCV schedules and reporting at least one clinical outcome. RCTs of 3p+1 schedules were carried out in high-income countries (Finland, USA) using PCV7, while RCTs of 3p+0 schedules were performed in lowor middle-income countries (Gambia, South Africa, Philippines) using investigational PCV9 or PCV11, respectively.
A further 5 RCTs compared catch-up (toddler) schedules to no PCV immunization. Otitis media was the only clinical outcome reported for most of these 5 RCTs. For IPD caused by vaccine serotypes, vaccine efficacy (VE) estimates for 3p+0 schedules were 71% (95% CI, 52%?82%, I2 0%, 2 RCTs) and for 3p+1 schedules 93% (95% CI, 76%?98%, I2 0%, 2 RCTs) using intention-totreat (ITT) data in individually randomized trials, and 86% (95% CI, 40%?97%) in the cluster-randomized trial (3p+1). Estimates were similar in HIV-infected and HIVuninfected infants vaccinated with a 3p+0 schedule.
For radiologically confirmed pneumonia (first episode), estimated VE for 3p+0 schedules using ITT data was 24% (95% CI, 9%?37%, I2 70%, 2 RCTs); the heterogeneity was not explained by the inclusion of HIV-infected children. For 3p+1 using ITT data, VE was 25% (95% CI, 6%?41%, 1 trial).
For otitis media, only 3p+1 and catch-up schedules were investigated. 3p+1 schedules protected against pneumococcal (VE 46%, 95% CI, 10%?55%, I2 17%, 2 RCTs) but not all-cause otitis media (VE 6%, 95% CI, 4%?9%, I2 0%) in healthy children (ITT data).
Generally, few deaths were reported in RCTs, with only 2 reporting >25 deaths. In both of these RCTs, fewer deaths occurred in the vaccinated group. In the Gambia, vaccination reduced overall all-cause mortality by 16% (95% CI, 3%?28%) (per-protocol data) using the investigational PCV9 vaccine.(9)
There are no published studies directly comparing PCV10 and PCV13, and so far, an effectiveness study is available only for PCV13. In England and Wales, where PCV13 replaced PCV7 in April 2010, effectiveness was estimated for the 6 new serotypes included in PCV13. The effectiveness for 2 doses in age group <1 year was 78% (95% CI, 18%−96%) and for 1 dose (age group >1 year) 77% (95% CI, 38%?91%). Vaccine effectiveness for 7F and 19A was 76% (21%?93%) and 70% (10%?90%) respectively, for ≥1 dose. Vaccine effectiveness for serotypes 1 and 3 was 62% and 66% respectively, although confidence intervals spanned zero. IPD due to PCV13-only serotypes halved in children aged <2 years in the study period.(28)
Optimal schedules
Currently, countries using PCVs in their routine immunization programmes choose with similar frequency the 3p+0, 2p+1, or 3p+1 schedules. The systematic reviews cited above(26, 27) found substantial evidence in support of using a 3p+0 (and 3p+1) schedule(s) which in these studies were administered typically at 6, 10, and 14 weeks or 2, 4, and 6 months (plus a booster at 1?2 years of age with the 3p+1 schedule).
Emerging evidence also supports the use of 2p+1 as an alternative schedule, with the third dose (the +1 dose) given between 9 and 15 months. Data from observational studies and post-introduction evaluation have reported high levels of protection against IPD following this schedule.(29) In a 2-dose schedule with PCV7, the 2-month interval group (vaccine given at 2 months and at 4 months of age) had higher levels of seropositivity 1 month after vaccination than the 1-month interval group (2-month and 3-month schedules). Similar results were seen at 12 months of age.(30)
There is some evidence for the additional benefit of a booster dose in terms of immunogenicity, reduced nasopharyngeal carriage of vaccine type serotypes, and prevention of invasive pneumococcal disease. For certain serotypes (e.g. 6B, 23F), 2p+1 may result in lower antibody levels than 3p+0 during the interval between the last primary dose and the booster dose. In contrast, higher antibody levels are induced by the third (booster) dose in a 2p+1 schedule compared to the third dose in a 3p+0 schedule. This boosting effect may be important for duration of protection and effectiveness against certain serotypes (e.g. serotype 1). However, additional studies are needed to evaluate these potential benefits of the 2p+1 schedule in developing country settings.
Evidence suggests that differences in clinical outcomes between 3p+0 and 2p+1 may be minimal in the presence of herd protection.
Co-administration
The immunogenicity and reactogenicity of the involved vaccines have been shown not to be significantly altered when PCVs are given concomitantly with monovalent or combination vaccines against diphtheria, tetanus, pertussis (acellular and whole-cell vaccines), hepatitis B, polio (inactivated and live oral vaccines), Hib, measles, mumps, rubella, varicella, meningococcus serogroup C (conjugate vaccine), and rotavirus.(22, 23)
Duration of protection
In South Africa, results of surveillance showed that 6.3 years after vaccination with a 9-valent vaccine, vaccine efficacy remained significant against IPD (78%; 95% CI, 34%?92%). This was consistent with immunogenicity data showing that specific antibody concentrations among HIV-uninfected children remained above the assumed protective levels compared to unvaccinated HIV-uninfected controls during this period. HIVinfected children who had received a 9-valent PCV at 6, 10 and 14 weeks of age showed some evidence of waning immunity over a mean follow-up period of 2.3 years with serotype-specific IgG levels below 0.35 μg/ml; the levels were not significantly different between vaccine recipients and controls for 3 of 7 serotypes evaluated.(31)
However, at follow up about 5 years after vaccination these vaccinees demonstrated a partial loss of anamnestic responses to PCV.(32)
Impact of PCVs on serotype replacement
A review of available surveillance data from Australia, Canada, England and Wales, South Africa and the USA collected during the period 1998?2009 showed rapid and substantial reductions of IPD caused by PCV-serotypes of the target group for vaccination (children aged <5 years) in all settings, although the magnitude of reductions from the pre-vaccine baseline varied. Reduction in IPD was evident also in individuals older than the targeted age group for vaccination (reflecting herd protection). For IPD caused by non-PCV serotypes, increases were evident among hospitalized cases aged <5 years in some settings and also for some age groups in the non-targeted population. For IPD caused by any serotype the incidence was reduced among those aged <5 years in all settings whereas for older age groups some settings experienced decreases, some no change, and one setting experienced an increase in some age strata.(33)
Non-vaccine factors may influence recorded rates of serotype-specific disease and thereby confound interpretation of the relationship between PCV introduction and serotype changes. Such factors include variation in the proportion of isolates serotyped before and after vaccine introduction, changes in blood culture practice, and outbreaks of pneumococcal disease. Thus there is a need for caution in interpreting pneumococcal disease surveillance data.(33)
Safety of PCVs
The favourable safety profile of PCV7 vaccine is well established.(34, 35) Several studies have shown that PCV10 and PCV13 have similar safety profiles to that of PCV7 when administered to infants and young children.(36, 37, 38,39, 40, 41) In a study of 4429 healthy infants who received PCV13 co-administered with routine paediatric vaccines, injection-site reactions, fever, irritability, decreased appetite, and increased and/or decreased sleep occurred in about 10% of the vaccinees). Injection site reactions were reported more often in children aged >12 months compared to rates observed in infants.
Pyrexia >39 ?C was observed (1/100 to <1/10), vomiting and diarrhoea in 1/1000 to <1/100, and hypersensitivity reactions (including rash, facial oedema, dyspnoea) and nervous system disorders (including convulsions and hypotonic-hyporesponsive episodes) were reported in 1/10 000 to <1/1000 of the vaccinees.(23) A review of 5 randomized controlled studies including a total of 4004 vaccinees concluded that the safety and reactogenicity profiles of PCV10 and PCV7 were within the same range when administered for primary and booster vaccination in coadministration with other routinely used paediatric vaccines.(36)
If immunization using both a PCV and PPV23 is considered appropriate in immunodeficient individuals ≥2 years, to avoid induction of hyporesponsiveness the PCV should always be administered first, allowing an interval of at least 2 months before the PPV23 booster.
Individuals with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes, may have a reduced antibody response to active immunization. Safety, efficacy, and immunogenicity data for individuals with increased risk for pneumococcal infections (e.g. sickle cell disease, congenital and acquired splenic dysfunction, HIV infection, malignancy, nephrotic syndrome) are not yet available for these vaccines.
Although there is no information on the safety of PCV10 and PCV13 during pregnancy in humans, animal studies do not indicate direct or indirect harmful effects of PCV with respect to reproductive toxicity.(22, 23)
PCV10 and PCV13 are contraindicated in individuals with known hypersensitivity to the active substances, the excipients, or to any of the carrier proteins. As with other vaccines, the administration of PCVs should be postponed in subjects suffering from acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in deferral of the vaccination.
Cost?effectiveness
A recent review(42) compared publicly available PCV decision-making tools in relation to the WHO guidelines for economic evaluations of immunization programmes.(43) The results were compared based on a standardized set of input parameters and assumptions.
Vaccine cost (dose price and number of doses), vaccine efficacy, and epidemiology of critical endpoints (e.g. incidence of pneumonia, distribution of serotypes causing pneumonia) were influential parameters in the models compared. A review of 15 economic analyses of pneumococcal conjugate vaccines published between 2002 and 2006, found a great diversity in assumptions (e.g. vaccine efficacy parameters, incidence rates for both invasive and noninvasive disease) mainly due to local variation in data and opinions.(44) Accordingly, the results varied greatly, from total net savings to a cost of over ?100 000 per discounted QALY gained. The cost of the vaccination programme (determined by price per dose and schedule, 4 or 3 doses, or fewer), and likely herd immunity impacts are highly influential though rarely explored in these published studies. The authors concluded that if the net long-term impact (determined by a mixture of effects related to herd immunity, serotype replacement, antibiotic resistance and cross reactivity) remained beneficial, and if a 3-dose schedule conferred nearequivalent protection to a 4-dose schedule, the costeffectiveness of vaccination programmes using (the then available) PCV7 could be viewed as attractive in developed countries.
WHO position
Currently available PCVs are safe and efficacious and the increased number of serotypes present in these vaccines, compared to the first licensed PCV7, represent significant progress in the fight against pneumococcal morbidity and mortality, in particular from a developing country perspective.(45, 46)
WHO recommends the inclusion of PCVs in childhood immunization programmes worldwide. In particular, countries with high childhood mortality (i.e. under 5 mortality rate of >50 deaths/1000 births) should make the introduction of these multicomponent PCVs a high priority.
The use of pneumococcal vaccine should be seen as complementary to the use of other pneumonia control measures, such as appropriate case management, promotion of exclusive breastfeeding for first 6 months of life, and the reduction of known risk factors, such as indoor pollutants and tobacco smoke.(18)
Planning for national use of pneumococcal vaccines should take into consideration the locally or regionally available estimates of disease burden, age distribution of cases, as well as the distribution of pneumococcal serotypes in different age groups.
PCV10 and PCV13 have comparable safety and efficacy profiles for the serotypes contained in the vaccines. The choice of PCV vaccine depends on factors such as the vaccine serotypes compared to serotypes prevalent in the locally identified target groups, vaccine supply, and cost-effectiveness considerations.
When primary immunization is initiated with one of these vaccines, it is recommended that remaining doses are administered with the same product. Interchangeability between PCV10 and PCV13 has not yet been documented. However, if it is not possible to complete the series with the same type of vaccine, the other PCV product should be used.
For PCV administration to infants, WHO recommends 3 primary doses (the 3p+0 schedule) or, as an alternative, 2 primary doses plus a booster (the 2p+1 schedule).(47) In choosing between the 3p+0 and 2p+1 schedules, countries should consider locally relevant factors including the epidemiology of pneumococcal disease, the likely coverage, and the timeliness of the vaccine doses.
If disease incidence peaks in young infants (<32 weeks of age), a 2p+1 schedule might not offer optimal individual protection for certain serotypes (e.g. 6B, 23F) compared to a 3p+0 schedule, particularly in the absence of herd protection. In contrast, higher antibody levels are induced by the third (booster) dose in a 2p+1 schedule compared to the third dose in a 3p+0 schedule. This may be important for duration of protection or effectiveness against some serotypes. The magnitude of herd protection after implementation of a pneumococcal conjugate immunization programme will depend on the immunization strategy, the coverage achieved, the degree of reduction in carriage of vaccine serotype pneumococci among vaccinees and their contacts, the proportion of pneumonias caused by vaccine serotypes, and the population composition.
If the 3p+0 schedule is used, vaccination can be initiated as early as 6 weeks of age with an interval between doses of 4?8 weeks, with doses given at 6, 10, and 14 weeks or at 2, 4, and 6 months, depending on programmatic convenience.
If the 2p+1 schedule is selected, the 2 primary doses should be given during infancy as early as 6 weeks of age at an interval preferably of 8 weeks or more for the youngest infants and 4?8 weeks or more between primary doses for infants aged ≥7 months. One booster dose should be given between 9?15 months of age. Previously unvaccinated or incompletely vaccinated children who recover from invasive pneumococcal disease should be vaccinated using the recommended age-appropriate regimens. HIV-positive infants and pre-term neonates who have received their 3 primary vaccine doses before reaching 12 months of age may benefit from a booster dose in the second year of life. Interrupted schedules should be resumed without repeating the previous dose.
Catch-up vaccination as part of introduction will accelerate herd protection and therefore the PCV impact on disease and carriage.
Maximized protection at the time of introduction of PCV10 or PCV13 can be achieved by providing 2 catch-up dose(s) at an interval of at least 2 months to unvaccinated children aged 12?24 months and to children aged 2?5 years who are at high risk of pneumococcal infection. When injected at different sites, PCVs can be administered concurrently with any other vaccines in infant immunization programmes.
PCVs are considered safe in all target groups for vaccination, also in immunocompromised individuals. The vaccines are not currently licensed for use in age groups that include women of childbearing age. Although theoretically highly unlikely to be harmful, there is no information on the safety of PCV10 and PCV13 during pregnancy.
Except for very rare anaphylactic reactions that may follow the administration of any medicine, there are no contraindications to the use of these vaccines. However, it is advisable to defer vaccination until after an acute infection with temperature >39 ?. Further data are needed from different epidemiological settings on the impact of large-scale PCV vaccination of individuals >50 years of age in order to establish the relative priority of immunization programmes in that age group. However, given the documented effects of herd protection in adult age groups following routine infant immunization with PCV7, higher priority should normally be given to introducing and maintaining high coverage of infants with PCVs.
In resource-limited settings where there are many competing health priorities, evidence does not support routine immunization of the elderly and high-risk populations with PPV23. Also, because of the low level of evidence for benefit, routine PPV23 vaccination of HIVinfected adults is not recommended in such settings. In countries that do not routinely administer PPV23 to high-risk populations, data are insufficient to recommend introducing this vaccine to reduce the morbidity and mortality associated with influenza.(48)
Health workers and travellers are not at increased risk for serious pneumococcal disease.
WHO recommends that the epidemiological impact of PCV be carefully monitored as part of routine sentinel surveillance. Serotype replacement should not be an impediment to PCV introduction; the observed increases in non-vaccine serotype IPD with the use of PCV7 are likely to be further mitigated by the use of PCVs with broader serotype coverage.
When interpreting observations of changing rates of non-vaccine type IPD, one must consider the larger context of overall IPD rates, variability of observations in pneumococcal epidemiology across sites and over time, differences in surveillance methods and in environmental factors, and all possible explanations for increases in non-vaccine-type pneumococcal disease, including but not limited to the use of PCV.
High-quality surveillance should be conducted in selected countries and defined populations that represent different epidemiological profiles worldwide. Surveillance of disease incidence should begin at least 2 years prior to PCV introduction and continue for at least 5 years post-introduction. However, lack of populationbased surveillance should not be an impediment to PCV introduction.
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Weekly epidemiological record / Relev? ?pid?miologique hebdomadaire
6 april 2012, 87th year / 6 avril 2012, 87e ann?e - No. 14, 2012, 87, 129?144 - http://www.who.int/wer
Pneumococcal vaccines - WHO position paper ? 2012
In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with the current WHO position on the use of vaccines worldwide.
The papers have been reviewed by external experts and WHO staff, and are reviewed and endorsed by the WHO Strategic Advisory Group of Experts on Immunization (SAGE) (http://www.who.int/immunization/sage/en/ ). The position papers are designed to be used mainly by national public health officials and managers of immunization programmes. They may also be of interest to international funding agencies, vaccine manufacturers, the medical community, the scientific media and the public.
The current document replaces the 2007 position paper on 7-valent pneumococcal conjugate vaccine. Incorporating the most recent developments in the field of pneumococcal vaccines this position paper focuses on the currently available 10-valent and 13-valent conjugate vaccines and their introduction and use in national immunization programmes. It also deals with the 23-valent polysaccharide vaccine, though in less detail than provided in the April 2008 position paper which remains valid.
Recommendations on the use of pneumococcal vaccines were discussed by SAGE at its meetings in November 2006 (conjugate vaccine) and April 2008 (polysaccharide vaccine) and most recently in November 2011. Evidence presented at these meetings can be accessed at http://www.who.int/immunization/sage/previous/en/index.html .
Epidemiology
Pneumococcal infections include serious diseases such as meningitis, bacteraemia, and pneumonia, as well as milder but more common illnesses, such as sinusitis and otitis media. The causative agent, Streptococcus pneumoniae, frequently colonizes the human nasopharynx, and is transmitted mainly through respiratory droplets. Infants and young children are thought to be the main reservoir of this agent with cross-sectional point prevalences of nasopharyngeal carriage ranging from 27% in developed to 85% in developing countries.
S. pneumoniae includes >90 serotypes. The distribution of serotypes that cause disease varies by age, disease syndrome, disease severity, geographic region, and over time. Prior to introduction of pneumococcal conjugate vaccines, 6?11 serotypes accounted for ≥70% of all invasive pneumococcal disease (IPD) occurring in children worldwide.(1) IPD is commonly defined as morbidity associated with the isolation of pneumococci from a normally sterile body site, such as the blood stream, or those secondary to blood stream spread, e.g. meningitis or septic arthritis; it does not include sites such as the middle ear which are infected by contiguous spread from the nasopharynx.
Most illnesses are sporadic. Outbreaks of pneumococcal disease are uncommon, but may occur in closed populations, such as nursing homes, childcare centres, or other institutions. However, large outbreaks of meningitis caused by serotype 1 have been reported from the African meningitis belt.(2)
Of the estimated 8.8 million global annual deaths amongst children <5 years of age in 2008, WHO estimated that 476 000 (333 000?529 000) were caused by pneumococcal infections.(3) Disease rates and mortality are higher in developing than in industrialized settings, with the majority of deaths occurring in Africa and Asia. Children with HIV infection are at substantially increased risk of serious pneumococcal disease.(4, 5)
Before widespread immunization with 7-valent pneumococcal conjugate vaccine, the mean annual incidence of IPD in children aged <2 years was 44.4/100 000 per year in Europe and 167/100 000 in the United States.(6, 7) In comparison, the annual incidence of IPD in children <2 years in Africa ranged from 60/100 000 in South Africa prior to the HIV epidemic to 797/100 000 in Mozambique.(5, 8, 9)
Some of the differences could be explained by differences in case ascertainment and surveillance sensitivity, though incidence in Africa did appear to be generally higher than in Europe or North America.
In Europe and the United States, S. pneumoniae is estimated to cause approximately 30%?50% of community-acquired pneumonia (CAP) requiring hospitalization in adults. In children, pneumococcal species were found in 78% and 13% of the cases respectively, among the 284 cases of lobar pneumonia and the 515 cases of bronchopneumonia proven to be of bacterial etiology by transthoracic needle aspiration.(10) In children <2 years of age a systematic Cochrane review of pneumococcal conjugate vaccines showed a pooled vaccine efficacy of 27% (95% CI, 15%?36%) against all cause pneumonia as defined by a WHO ? consensus case definition.(11)
There is a temporal relation between the incidences of CAP and documented circulation of influenza and respiratory syncytial viruses.(12)
In many countries routine use of pneumococcal conjugate vaccines has dramatically reduced the incidence of IPD and in some places IPD caused by vaccine serotypes has virtually disappeared, even in age groups not primarily targeted by the immunization programme (herd immunity effect).(13)
Pathogen
S. pneumoniae is a Gram-positive, encapsulated diplococcus. The polysaccharide capsule of this bacterium is an essential virulence factor and the >90 distinct pneumococcal serotypes are defined on the basis of differences in the composition of this capsule. In general, immunity following infection is serotype-specific, but cross-protection between related serotypes can occur. While a wide variety of serotypes cause non-invasive diseases such as otitis media and sinusitis, serotypes 1, 5, 6A, 6B, 14, 19F, and 23F are common causes of IPD globally in children <5 years of age. Serotypes 1, 5, and 14 together account for 28%?43% of IPD across regions and for about 30% of IPD in 20 of the world?s poorest countries; serotypes 23F and 19F are responsible for 9%?18% of cases globally. Serotype 18C is common in regions with a large proportion of high-income countries (i.e., Europe, North America, and Oceania).(1) Some serotypes such as 6B, 9V, 14, 19A, 19F, and 23F are more likely than others to be associated with drug resistance.(14)
Laboratory diagnosis of S. pneumoniae based on growth in culture media can be made in most clinical microbiology laboratories, although prior antibiotic treatment, improper handling or transport of specimens, or use of inappropriate culture media, may result in failure to isolate the organism. Some of the observed geographical variation in serotype distribution may be attributable to factors including differences in selection of patients, the frequency and quality of blood-culture, pneumococcal vaccination programmes, and antibiotic policy.(15)
Disease
Pneumococcal infection and disease can affect a variety of organ systems resulting in a number of disease syndromes. Although temporary colonization of the nasopharyngeal mucosa, which is the primary focus of infection, rarely results in disease, certain pneumococcal serotypes may occasionally invade the blood stream causing bacteraemia and possibly infection of secondary sites such as the meninges. In other instances, contiguous spread from the nasopharynx may cause diseases such as otitis media or sinusitis. Pneumonia is often caused by aspiration of pneumococci from the nasophaynx. When associated with bacteraemia, pneumonia is classified as IPD.(16)
Due to its unambiguous microbiological diagnosis, the incidence of IPD is frequently used as a measure of the incidence of severe pneumococcal disease in general. On average, about 75% of IPD cases and 83% of pneumococcal meningitis occur in children aged <2 years, but these incidences vary considerably, as does the distribution of cases in age strata below 2 years. For pneumonia, between 8.7% and 52.4% of cases occur in infants aged <6 months.(16)
Case fatality rates (CFR) can be high for IPD, ranging up to 20% for septicaemia and 50% for meningitis in developing countries. Mortality is greatest in younger infants. Even in industrialized countries, the overall CFR for pneumococcal bacteraemia may reach 15%?20% among adults and 30%?40% among elderly patients, despite appropriate antibiotic therapy and intensive care. Among meningitis survivors, long-term neurological sequelae such as hearing loss, mental retardation, motor abnormalities and seizures have been observed in frequencies as high as 58% of cases.(17) Pneumococcal middle-ear infection and sinusitis are less severe, but they are considerably more common health problems worldwide.
Lack of exclusive breastfeeding, nutritional deficiencies, and indoor air pollution are risk factors for pneumonia, including pneumococcal pneumonia, in infants and young children.(18) Apart from the high incidence in children <2 years of age, the risk for pneumococcal disease is increased in the elderly (>65 years of age), and in people who use tobacco or alcohol excessively. This risk is also increased in individuals who suffer from chronic medical conditions, such as heart disease, lung disease, diabetes, or asplenia, or from other conditions that suppress the immune system, such as advanced HIV infection. Development of pneumococcal resistance to commonly used antibiotics such as penicillins, macrolides, cephalosporins, and co-trimoxazole is a serious problem in some parts of the world. However, following the introduction of large-scale pneumococcal immunization a reduction in the circulation of drug-resistant strains has been observed.(14)
A definitive diagnosis of pneumococcal infection can be made by isolating the bacterium from blood or other normally sterile body sites, such as cerebrospinal fluid, but the etiological diagnosis is problematic in cases of non-bacteraemic pneumococcal pneumonia.
Pneumococcal vaccines
Vaccines have been used to prevent pneumococcal disease for more than 30 years. Currently, there are 2 different types of pneumococcal vaccines on the market:
(1) a 23-valent polysaccharide vaccine (PPV23) available since the early 1980s and
(2) 2 conjugate vaccines available since 2009, one 10-valent (PCV10) the other 13-valent (PCV13).
The 7-valent conjugate vaccine (PCV7) is gradually being removed from the market.
Pneumococcal polysaccharide vaccines are associated with poor or absent immunogenicity in children <2 years of age and failure at any age to induce an anamnestic antibody response upon revaccination. The term pneumococcal conjugate vaccine refers to vaccines based on chemical coupling of S. pneumoniae polysaccharides to an immunogenic protein carrier. This enhances the antibody response and induces immune memory.
23-valent pneumococcal polysaccharide vaccine
PPV23 includes the serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B,17F, 18C, 19A, 19F, 20, 22F, 23F and 33F. For primary immunization, PPV23 is administered as a single intramuscular or subcutaneous dose. Revaccination is not normally recommended in immunologically healthy individuals, but 1 or 2 revaccinations have been practiced in immunocompromised individuals.(13)
In some high- or middle-income countries PPV23 is recommended for populations proven to be at increased risk of morbidity and mortality from pneumococcal infection, including adults aged >65 years. PPV23 is also used to supplement the immune response following primary vaccination with one of the pneumococcal conjugate vaccines (see below). Developing countries have not made the use of PPV23 a priority.
Comprehensive meta-analyses of studies assessing PPV23 vaccine efficacy and effectiveness have been conducted, including a 2007 WHO-commissioned meta-analysis and a review of randomized controlled trials (RCTs).(19, 20) On balance, as shown in the meta-analyses, the results of the RCTs of PPV23 are consistent with a protective effect against IPD and all-cause pneumonia among generally healthy young adults and, to a lesser extent, protection against IPD in the general population of elderly people. Such trials have not demonstrated that PPV23 is efficacious against either IPD or all-cause pneumonia in populations at higher risk, such as adults and children with underlying conditions that increase their risk of pneumococcal disease or highly immunosuppressed individuals of any age.(20)
PPV23 is considered safe both in terms of severe immediate reactions and potential long-term adverse consequences.
Detailed information on the PPV23 is provided in the position paper published in 2008.(21) Key conclusions are also stated in the final WHO position in the current text.
Conjugate vaccines
This position paper focuses on PCV10 and PCV13 and their use in children. Evidence in support of the use of PCVs for immunization of older populations and the potential use of such vaccines for immunization in pregnancy to protect newborn babies is currently not considered sufficient to support policy recommendations, but will be reviewed regularly as part of the process of updating the position papers. PCV10 is composed of the capsular polysaccharides purified from 10 serotypes: 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Each is conjugated to a carrier protein, either protein D (an outer membrane protein from non-typable Haemophilus influenzae), tetanus toxoid, or diphtheria toxoid. Protein D is used as carrier protein for 8 of the 10 serotypes (serotypes 1, 4, 5, 6B, 7F, 9V, 14 and 23F); serotype 19F is conjugated to diphtheria toxoid and serotype 18C is conjugated to tetanus toxoid. PCV10 is adjuvanted with aluminium phosphate, and presented in a single dose syringe or as 1 or 2 dose vial.
Latex is contained within the syringe component. The volume per dose is 0.5ml. Each dose contains 1 μg of polysaccharide for serotypes 1, 5, 6B, 7F, 9V, 14 and 23F, and 3 μg of serotypes 4, 18C and 19F. PCV13 contains polysaccharide antigens of the pneumococcal capsular serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, individually conjugated to a nontoxic diphtheria CRM 197 (CRM, cross-reactive material) carrier protein. A 0.5ml PCV13 dose contains approximately 2 μg of polysaccharide from each of 12 serotypes and approximately 4 μg of polysaccharide from serotype 6B. The vaccine contains aluminium phosphate as adjuvant. PCV13 is available in single dose, pre-filled syringes that do not contain latex and in single dose vials.(22, 23)
Both PCV10 and PCV13 are preservative-free, their recommended storage temperature is 2?8 ?C, and the vaccines must not be frozen.
A systematic review and meta-analysis of IPD serotype data obtained from children <5 years of age during the period 1980?2007, i.e. before national PCV7 introduction, showed that the serotypes included in PCV7 accounted for ≥49% of IPD in each geographic region, although with substantial regional variation (range: 49%?82%), with highest serotype coverage in North America and Europe. The corresponding estimated coverage for serotypes included in PCV10 and PCV13 reached ≥70% of IPD in every region (range: 70%?84% and 74%?88%, respectively).
Indication and administration
Although the exact labelling details may differ by country, both PCV10 and PCV13 are licensed for active immunization for the prevention of invasive disease, pneumonia and acute otitis media caused by the respective vaccine serotypes of S. pneumoniae in infants and children from 6 weeks to 5 years of age. In addition, PCV13 is licensed for the prevention of pneumococcal disease in adults >50 years of age.(22, 23)
PCVs are not indicated for treatment of pneumococcal disease and are unlikely to prevent infection caused by S. pneumoniae serogroups that are not included in the vaccines. The immune responses to the PCV carrier proteins diphtheria cross-reactive protein (PCV13), and tetanus and diphtheria toxoids (PCV10), have not been studied. However, with PCV10, one trial showed a protective effect (35.3%; 95% CI, 1.8-57.4) against otitis media caused by non-typable H. influenzae, possibly attributable to the vaccine?s H. influenzae-derived carrier protein.(24)
The vaccines are given by injection into the anterolateral aspect of the thigh in infants and into the deltoid muscle in older age groups. For PCV10 and PCV13, the manufacturers recommend 3 primary doses with an interval of at least 4 weeks between doses, plus a booster at least 6 months after the third dose (3p+1 schedule). The first can be given as early as 6 weeks of age; the booster dose is given preferably between 11 and 15 months of age. An alternative schedule consists of 2 primary doses given 2 months apart, starting at 2 months of age, followed by a booster at least 6 months after the second dose (2p+1 schedule).
The manufacturers further recommend that previously unvaccinated infants aged 7?11 months should receive 2 doses, the second dose at least 4 weeks after the first, followed by a third dose in the second year of life. For PCV10, unvaccinated children 12 months to 5 years of age should receive 2 doses, with an interval between the first and second dose of at least 2 months. For PCV13, unvaccinated children aged 12?24 months should receive 2 doses, children aged 2?5 years should receive a single dose; adults >50 years of age should receive a single dose.
A variety of off-label schedules have been evaluated, as discussed later in this paper, and some of these are being used in national immunization programmes.
Serological criteria for evaluation of pneumococcal conjugate vaccines
Results of studies on vaccine efficacy or effectiveness against IPD, otitis media, or pneumonia were not available at the time of initial licensure of PCV10 and PCV13. Since non-inferiority trials comparing these vaccines against PCV7, using clinical end-points, would require very large sample sizes and would be prohibitively expensive, licensure both of PCV10 and PCV13 was based on non-inferiority trials using serological end-points. These trials demonstrated similar immunogenicity profiles between the latter vaccines and PCV7 against most of their common serotypes, as well as a favourable immunogenicity profile also for the additional serotypes of PCV10 and PCV13.
For the serotypes common to the new vaccine and the licensed comparator, WHO has defined serological criteria for non-inferiority that should be used in the primary analysis.25 The criteria include (a) the percentage of subjects with serotype-specific IgG ≥0.35 μg/ml using a WHO reference assay (or an alternative and well-justified threshold value based on a specific in-house assay) and (b) the serotype-specific IgG geometric concentration ratios. In addition, in the secondary analysis, it is recommended that comparisons of opsonophagocytic antibody titres of serotypes that are common to the new vaccine and the licensed comparator should focus on serotype-specific geometric mean titres (GMT) ratios rather than the previously used threshold functional titer ≥1:8.
Outcomes of PCV immunization
Two recent systematic reviews(26, 27) have assessed clinical and immunological outcomes of PCV vaccination using data from RCTs and observational studies. Most of the available evidence presented in these reviews pertains to PCV7 or the investigational vaccines PCV9 and PCV11 although available studies on PCV10 and PCV13 were also included.
One review(26) identified 10 RCTs using either 3p+1 or 3p+0 PCV schedules and reporting at least one clinical outcome. RCTs of 3p+1 schedules were carried out in high-income countries (Finland, USA) using PCV7, while RCTs of 3p+0 schedules were performed in lowor middle-income countries (Gambia, South Africa, Philippines) using investigational PCV9 or PCV11, respectively.
A further 5 RCTs compared catch-up (toddler) schedules to no PCV immunization. Otitis media was the only clinical outcome reported for most of these 5 RCTs. For IPD caused by vaccine serotypes, vaccine efficacy (VE) estimates for 3p+0 schedules were 71% (95% CI, 52%?82%, I2 0%, 2 RCTs) and for 3p+1 schedules 93% (95% CI, 76%?98%, I2 0%, 2 RCTs) using intention-totreat (ITT) data in individually randomized trials, and 86% (95% CI, 40%?97%) in the cluster-randomized trial (3p+1). Estimates were similar in HIV-infected and HIVuninfected infants vaccinated with a 3p+0 schedule.
For radiologically confirmed pneumonia (first episode), estimated VE for 3p+0 schedules using ITT data was 24% (95% CI, 9%?37%, I2 70%, 2 RCTs); the heterogeneity was not explained by the inclusion of HIV-infected children. For 3p+1 using ITT data, VE was 25% (95% CI, 6%?41%, 1 trial).
For otitis media, only 3p+1 and catch-up schedules were investigated. 3p+1 schedules protected against pneumococcal (VE 46%, 95% CI, 10%?55%, I2 17%, 2 RCTs) but not all-cause otitis media (VE 6%, 95% CI, 4%?9%, I2 0%) in healthy children (ITT data).
Generally, few deaths were reported in RCTs, with only 2 reporting >25 deaths. In both of these RCTs, fewer deaths occurred in the vaccinated group. In the Gambia, vaccination reduced overall all-cause mortality by 16% (95% CI, 3%?28%) (per-protocol data) using the investigational PCV9 vaccine.(9)
There are no published studies directly comparing PCV10 and PCV13, and so far, an effectiveness study is available only for PCV13. In England and Wales, where PCV13 replaced PCV7 in April 2010, effectiveness was estimated for the 6 new serotypes included in PCV13. The effectiveness for 2 doses in age group <1 year was 78% (95% CI, 18%−96%) and for 1 dose (age group >1 year) 77% (95% CI, 38%?91%). Vaccine effectiveness for 7F and 19A was 76% (21%?93%) and 70% (10%?90%) respectively, for ≥1 dose. Vaccine effectiveness for serotypes 1 and 3 was 62% and 66% respectively, although confidence intervals spanned zero. IPD due to PCV13-only serotypes halved in children aged <2 years in the study period.(28)
Optimal schedules
Currently, countries using PCVs in their routine immunization programmes choose with similar frequency the 3p+0, 2p+1, or 3p+1 schedules. The systematic reviews cited above(26, 27) found substantial evidence in support of using a 3p+0 (and 3p+1) schedule(s) which in these studies were administered typically at 6, 10, and 14 weeks or 2, 4, and 6 months (plus a booster at 1?2 years of age with the 3p+1 schedule).
Emerging evidence also supports the use of 2p+1 as an alternative schedule, with the third dose (the +1 dose) given between 9 and 15 months. Data from observational studies and post-introduction evaluation have reported high levels of protection against IPD following this schedule.(29) In a 2-dose schedule with PCV7, the 2-month interval group (vaccine given at 2 months and at 4 months of age) had higher levels of seropositivity 1 month after vaccination than the 1-month interval group (2-month and 3-month schedules). Similar results were seen at 12 months of age.(30)
There is some evidence for the additional benefit of a booster dose in terms of immunogenicity, reduced nasopharyngeal carriage of vaccine type serotypes, and prevention of invasive pneumococcal disease. For certain serotypes (e.g. 6B, 23F), 2p+1 may result in lower antibody levels than 3p+0 during the interval between the last primary dose and the booster dose. In contrast, higher antibody levels are induced by the third (booster) dose in a 2p+1 schedule compared to the third dose in a 3p+0 schedule. This boosting effect may be important for duration of protection and effectiveness against certain serotypes (e.g. serotype 1). However, additional studies are needed to evaluate these potential benefits of the 2p+1 schedule in developing country settings.
Evidence suggests that differences in clinical outcomes between 3p+0 and 2p+1 may be minimal in the presence of herd protection.
Co-administration
The immunogenicity and reactogenicity of the involved vaccines have been shown not to be significantly altered when PCVs are given concomitantly with monovalent or combination vaccines against diphtheria, tetanus, pertussis (acellular and whole-cell vaccines), hepatitis B, polio (inactivated and live oral vaccines), Hib, measles, mumps, rubella, varicella, meningococcus serogroup C (conjugate vaccine), and rotavirus.(22, 23)
Duration of protection
In South Africa, results of surveillance showed that 6.3 years after vaccination with a 9-valent vaccine, vaccine efficacy remained significant against IPD (78%; 95% CI, 34%?92%). This was consistent with immunogenicity data showing that specific antibody concentrations among HIV-uninfected children remained above the assumed protective levels compared to unvaccinated HIV-uninfected controls during this period. HIVinfected children who had received a 9-valent PCV at 6, 10 and 14 weeks of age showed some evidence of waning immunity over a mean follow-up period of 2.3 years with serotype-specific IgG levels below 0.35 μg/ml; the levels were not significantly different between vaccine recipients and controls for 3 of 7 serotypes evaluated.(31)
However, at follow up about 5 years after vaccination these vaccinees demonstrated a partial loss of anamnestic responses to PCV.(32)
Impact of PCVs on serotype replacement
A review of available surveillance data from Australia, Canada, England and Wales, South Africa and the USA collected during the period 1998?2009 showed rapid and substantial reductions of IPD caused by PCV-serotypes of the target group for vaccination (children aged <5 years) in all settings, although the magnitude of reductions from the pre-vaccine baseline varied. Reduction in IPD was evident also in individuals older than the targeted age group for vaccination (reflecting herd protection). For IPD caused by non-PCV serotypes, increases were evident among hospitalized cases aged <5 years in some settings and also for some age groups in the non-targeted population. For IPD caused by any serotype the incidence was reduced among those aged <5 years in all settings whereas for older age groups some settings experienced decreases, some no change, and one setting experienced an increase in some age strata.(33)
Non-vaccine factors may influence recorded rates of serotype-specific disease and thereby confound interpretation of the relationship between PCV introduction and serotype changes. Such factors include variation in the proportion of isolates serotyped before and after vaccine introduction, changes in blood culture practice, and outbreaks of pneumococcal disease. Thus there is a need for caution in interpreting pneumococcal disease surveillance data.(33)
Safety of PCVs
The favourable safety profile of PCV7 vaccine is well established.(34, 35) Several studies have shown that PCV10 and PCV13 have similar safety profiles to that of PCV7 when administered to infants and young children.(36, 37, 38,39, 40, 41) In a study of 4429 healthy infants who received PCV13 co-administered with routine paediatric vaccines, injection-site reactions, fever, irritability, decreased appetite, and increased and/or decreased sleep occurred in about 10% of the vaccinees). Injection site reactions were reported more often in children aged >12 months compared to rates observed in infants.
Pyrexia >39 ?C was observed (1/100 to <1/10), vomiting and diarrhoea in 1/1000 to <1/100, and hypersensitivity reactions (including rash, facial oedema, dyspnoea) and nervous system disorders (including convulsions and hypotonic-hyporesponsive episodes) were reported in 1/10 000 to <1/1000 of the vaccinees.(23) A review of 5 randomized controlled studies including a total of 4004 vaccinees concluded that the safety and reactogenicity profiles of PCV10 and PCV7 were within the same range when administered for primary and booster vaccination in coadministration with other routinely used paediatric vaccines.(36)
If immunization using both a PCV and PPV23 is considered appropriate in immunodeficient individuals ≥2 years, to avoid induction of hyporesponsiveness the PCV should always be administered first, allowing an interval of at least 2 months before the PPV23 booster.
Individuals with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes, may have a reduced antibody response to active immunization. Safety, efficacy, and immunogenicity data for individuals with increased risk for pneumococcal infections (e.g. sickle cell disease, congenital and acquired splenic dysfunction, HIV infection, malignancy, nephrotic syndrome) are not yet available for these vaccines.
Although there is no information on the safety of PCV10 and PCV13 during pregnancy in humans, animal studies do not indicate direct or indirect harmful effects of PCV with respect to reproductive toxicity.(22, 23)
PCV10 and PCV13 are contraindicated in individuals with known hypersensitivity to the active substances, the excipients, or to any of the carrier proteins. As with other vaccines, the administration of PCVs should be postponed in subjects suffering from acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in deferral of the vaccination.
Cost?effectiveness
A recent review(42) compared publicly available PCV decision-making tools in relation to the WHO guidelines for economic evaluations of immunization programmes.(43) The results were compared based on a standardized set of input parameters and assumptions.
Vaccine cost (dose price and number of doses), vaccine efficacy, and epidemiology of critical endpoints (e.g. incidence of pneumonia, distribution of serotypes causing pneumonia) were influential parameters in the models compared. A review of 15 economic analyses of pneumococcal conjugate vaccines published between 2002 and 2006, found a great diversity in assumptions (e.g. vaccine efficacy parameters, incidence rates for both invasive and noninvasive disease) mainly due to local variation in data and opinions.(44) Accordingly, the results varied greatly, from total net savings to a cost of over ?100 000 per discounted QALY gained. The cost of the vaccination programme (determined by price per dose and schedule, 4 or 3 doses, or fewer), and likely herd immunity impacts are highly influential though rarely explored in these published studies. The authors concluded that if the net long-term impact (determined by a mixture of effects related to herd immunity, serotype replacement, antibiotic resistance and cross reactivity) remained beneficial, and if a 3-dose schedule conferred nearequivalent protection to a 4-dose schedule, the costeffectiveness of vaccination programmes using (the then available) PCV7 could be viewed as attractive in developed countries.
WHO position
Currently available PCVs are safe and efficacious and the increased number of serotypes present in these vaccines, compared to the first licensed PCV7, represent significant progress in the fight against pneumococcal morbidity and mortality, in particular from a developing country perspective.(45, 46)
WHO recommends the inclusion of PCVs in childhood immunization programmes worldwide. In particular, countries with high childhood mortality (i.e. under 5 mortality rate of >50 deaths/1000 births) should make the introduction of these multicomponent PCVs a high priority.
The use of pneumococcal vaccine should be seen as complementary to the use of other pneumonia control measures, such as appropriate case management, promotion of exclusive breastfeeding for first 6 months of life, and the reduction of known risk factors, such as indoor pollutants and tobacco smoke.(18)
Planning for national use of pneumococcal vaccines should take into consideration the locally or regionally available estimates of disease burden, age distribution of cases, as well as the distribution of pneumococcal serotypes in different age groups.
PCV10 and PCV13 have comparable safety and efficacy profiles for the serotypes contained in the vaccines. The choice of PCV vaccine depends on factors such as the vaccine serotypes compared to serotypes prevalent in the locally identified target groups, vaccine supply, and cost-effectiveness considerations.
When primary immunization is initiated with one of these vaccines, it is recommended that remaining doses are administered with the same product. Interchangeability between PCV10 and PCV13 has not yet been documented. However, if it is not possible to complete the series with the same type of vaccine, the other PCV product should be used.
For PCV administration to infants, WHO recommends 3 primary doses (the 3p+0 schedule) or, as an alternative, 2 primary doses plus a booster (the 2p+1 schedule).(47) In choosing between the 3p+0 and 2p+1 schedules, countries should consider locally relevant factors including the epidemiology of pneumococcal disease, the likely coverage, and the timeliness of the vaccine doses.
If disease incidence peaks in young infants (<32 weeks of age), a 2p+1 schedule might not offer optimal individual protection for certain serotypes (e.g. 6B, 23F) compared to a 3p+0 schedule, particularly in the absence of herd protection. In contrast, higher antibody levels are induced by the third (booster) dose in a 2p+1 schedule compared to the third dose in a 3p+0 schedule. This may be important for duration of protection or effectiveness against some serotypes. The magnitude of herd protection after implementation of a pneumococcal conjugate immunization programme will depend on the immunization strategy, the coverage achieved, the degree of reduction in carriage of vaccine serotype pneumococci among vaccinees and their contacts, the proportion of pneumonias caused by vaccine serotypes, and the population composition.
If the 3p+0 schedule is used, vaccination can be initiated as early as 6 weeks of age with an interval between doses of 4?8 weeks, with doses given at 6, 10, and 14 weeks or at 2, 4, and 6 months, depending on programmatic convenience.
If the 2p+1 schedule is selected, the 2 primary doses should be given during infancy as early as 6 weeks of age at an interval preferably of 8 weeks or more for the youngest infants and 4?8 weeks or more between primary doses for infants aged ≥7 months. One booster dose should be given between 9?15 months of age. Previously unvaccinated or incompletely vaccinated children who recover from invasive pneumococcal disease should be vaccinated using the recommended age-appropriate regimens. HIV-positive infants and pre-term neonates who have received their 3 primary vaccine doses before reaching 12 months of age may benefit from a booster dose in the second year of life. Interrupted schedules should be resumed without repeating the previous dose.
Catch-up vaccination as part of introduction will accelerate herd protection and therefore the PCV impact on disease and carriage.
Maximized protection at the time of introduction of PCV10 or PCV13 can be achieved by providing 2 catch-up dose(s) at an interval of at least 2 months to unvaccinated children aged 12?24 months and to children aged 2?5 years who are at high risk of pneumococcal infection. When injected at different sites, PCVs can be administered concurrently with any other vaccines in infant immunization programmes.
PCVs are considered safe in all target groups for vaccination, also in immunocompromised individuals. The vaccines are not currently licensed for use in age groups that include women of childbearing age. Although theoretically highly unlikely to be harmful, there is no information on the safety of PCV10 and PCV13 during pregnancy.
Except for very rare anaphylactic reactions that may follow the administration of any medicine, there are no contraindications to the use of these vaccines. However, it is advisable to defer vaccination until after an acute infection with temperature >39 ?. Further data are needed from different epidemiological settings on the impact of large-scale PCV vaccination of individuals >50 years of age in order to establish the relative priority of immunization programmes in that age group. However, given the documented effects of herd protection in adult age groups following routine infant immunization with PCV7, higher priority should normally be given to introducing and maintaining high coverage of infants with PCVs.
In resource-limited settings where there are many competing health priorities, evidence does not support routine immunization of the elderly and high-risk populations with PPV23. Also, because of the low level of evidence for benefit, routine PPV23 vaccination of HIVinfected adults is not recommended in such settings. In countries that do not routinely administer PPV23 to high-risk populations, data are insufficient to recommend introducing this vaccine to reduce the morbidity and mortality associated with influenza.(48)
Health workers and travellers are not at increased risk for serious pneumococcal disease.
WHO recommends that the epidemiological impact of PCV be carefully monitored as part of routine sentinel surveillance. Serotype replacement should not be an impediment to PCV introduction; the observed increases in non-vaccine serotype IPD with the use of PCV7 are likely to be further mitigated by the use of PCVs with broader serotype coverage.
When interpreting observations of changing rates of non-vaccine type IPD, one must consider the larger context of overall IPD rates, variability of observations in pneumococcal epidemiology across sites and over time, differences in surveillance methods and in environmental factors, and all possible explanations for increases in non-vaccine-type pneumococcal disease, including but not limited to the use of PCV.
High-quality surveillance should be conducted in selected countries and defined populations that represent different epidemiological profiles worldwide. Surveillance of disease incidence should begin at least 2 years prior to PCV introduction and continue for at least 5 years post-introduction. However, lack of populationbased surveillance should not be an impediment to PCV introduction.
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