Origin
Due to the problems inherent in PPV as described above (in particular the inability to use it in children aged less than two years and the lack of efficacy in preventing CAP), further vaccine developments were required. The immunogenicity of the polysaccharides contained with PPV can be enhanced by conjugating to a highly immunogenic protein,168 creating a pneumococcal conjugate vaccine (PCV).
Conjugation of a protein to the vaccine also promotes a T cell dependant response, inducing a memory T cell response, and hence the ability to use multiple doses to achieve a booster effect.169
The first PCV to be introduced to vaccination schedules was PCV-7, for use in infants less than two years of age, in three doses at two, four, and thirteen months. Only seven serotypes are included in the vaccine, in contrast to the 23 in PPV, although these seven are thought to include the majority of prevalent and invasive serotypes encountered in the USA (table 2.3). However, this is not the case in the rest of the world, particularly Africa and Asia, where these seven serotypes represent only 60%
and 45% of IPD serotypes respectively.101
Efficacy
Between 92% and 100% infants generate antibody after three PCV-7 doses.169 It has proven efficacy in reducing:
All-cause and pneumococcal OM in children;170, 171
Hospital or outpatient visits due to OM;172, 173
IPD in all children;174-176
IPD in vaccinated children;177-179
CAP in vaccinated infants;179, 180
All-cause and pneumococcal CAP hospital admissions in children;173, 181-183
PCV-7 serotype (VT) carriage in vaccinated infants;184-187
Pneumococcal VT carriage in household contacts of vaccinated infants;58, 184
45
Pneumococcal VT carriage in unvaccinated infants;188
Pneumococcal VT carriage in adults;52
VT and all cause IPD in adults;120, 176, 189
A recent meta-analysis incorporating these studies calculated a reduction in vaccinated children of 89% for VT IPD, 55-57% in VT OM, and 29-32% in radiographically confirmed CAP.190 Of particular note, PCV-7 reduces VT colonisation in unvaccinated contacts, and IPD in unvaccinated adults. This suggests that large scale vaccination of children may be promoting a “herd immunity” effect. In addition, all pneumococcal disease is thought to be preceded by nasopharyngeal carriage, and the highest rates of pneumococcal carriage are in children. Therefore, the reduction in pneumococcal carriage in children may be reducing transmission to adults, and thereby reducing adult pneumococcal disease. However, this theory is as yet unproven.
Serotype shift
PCV-7 contains only seven of the 91 pneumococcal serotypes.92 Thus while significant reductions are expected in VT serotypes across the pneumococcal disease spectrum, uncertainty surrounds the impact of vaccination on non-PCV-7 vaccine-type (NVT) serotypes. As discussed in the previous section, all-cause IPD rates have fallen following introduction of PCV-7. However, an increase in NVT and vaccine-related serotypes (defined as the same serogroup as a VT serotype, but different serotype;
for example, 19A and 19F) at the expense of VT serotypes has also been seen.
Several carriage studies have shown an increase in NVT serotypes concomitant with a decrease in VT serotypes.57, 58, 187, 191 IPD studies have shown an increase in the total number and proportion of cultured NVT serotypes, an effect seen in both PCV-7 vaccinated and unvaccinated children, and adults (table 2.6). Of note, serotype 19A has significantly increased in incidence in the majority of IPD studies. Increases in the NVT serotype 19A in otitis media in children in one study interestingly started to occur before the introduction of PCV-7.192 Antibiotic resistance within this group also
46 increased from 10% to 50% over the study period, implying that this increase may have been driven by antibiotic over-use.
47 Vaccine Serotypes covered
PPV 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F
PCV-7 4, 6B, 9V, 14, 18C, 19F, 23F PCV-9 1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F PCV-10 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F PCV-11 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F
PCV-13 1, 3 ,4 , 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F
Shared serotypes are in bold. PPV: pneumococcal polysaccharide vaccine; PCV:
pneumococcal conjugate vaccine.
Table 2.5. Pneumococcal vaccine serotype coverage.
48
Study Setting N Time
period Emergent serotypes Reduction in
VT disease
“children”: those aged less than 5 years.
Table 2.6. Studies showing a serotype shift in invasive pneumococcal disease since introduction of PCV-7.
48
49 Serotype shift has been implicated in a change in the spectrum of clinical disease, primarily in children. An increase has been documented in the incidence of a serious complication of CAP, para-pneumonic empyema, in the USA in children from 2.2 per 100,000 to 3.7 per 100,000 following the introduction of PCV-7,205, 206 and this has primarily been caused by NVT serotypes 1, 3 and 19A.207 However, the incidence of empyema also increased in the decade prior to introduction of PCV-7 in Israel (from 0.5 to 4.2 per 100,000 children), mainly due to serotype 1,208 suggesting that epidemiological factors may also be implicated in this change. An increase in culture-positive pneumococcal necrotizing pneumonia from 13% pre-PCV-7 to 33% post-PCV-7 has been observed in children in Utah, USA, accompanied by an increase may be causing changes in the clinical disease spectrum, both by an increase in CAP complications such as empyema, and a reduction in mortality. However, the evidence for this effect to date is scanty, and may not be representive of non-invasive CAP, which forms the majority of disease. A rigorous observational study is required, linking the change in pneumococcal serotypes following the introduction of PCV-7 with a change in the clinical spectrum and outcome of invasive and non-invasive pneumococcal CAP.