17. Pneumococcal disease

The human nasopharynx is the only natural reservoir of S. pneumoniae. Transmission is by contact with respiratory droplets. Carriage rates in young children range from 21 percent in high-income settings to more than 90 percent in resource-limited countries.[1] Although nasopharyngeal colonisation precedes disease, most who are colonised do not develop disease. The period between colonisation with S. pneumoniae and infection is variable but may be as short as one day. Transmission and invasive potential are increased by concomitant viral upper respiratory tract infection, especially influenza.

Pneumococcal disease is a common cause of morbidity and mortality worldwide. Rates of disease and death are highest in low-income countries with the majority of deaths occurring in sub-Saharan Africa and Asia.[2] Along with the very old and very young, patients with underlying cardiorespiratory disease and congenital or acquired immunosuppression have the highest rates of disease.

Risk of disease increases with multiple comorbidities and lifestyle factors (this is described as risk-stacking, see section 17.5.4).[3] The risk of IPD in children and adults with two or more comorbid conditions can be as high as in those with a recognised ‘high-risk’ condition.[4] Lifestyle factors, such as passive smoking, environmental and workplace pollutions, smoking and alcohol dependency, can increase the risk of severe pneumococcal disease, especially in those with chronic illnesses that predispose them to infection, such as asthma, diabetes, dementia and mental illness.[5, 6] Socioeconomic deprivation, homelessness and overcrowding have also been associated with increased risk of IPD.[7]

The WHO estimates that 300,000 (range 200–370,000) children aged under 5 years died from pneumococcal infections, representing around 5 percent of all-cause mortality in this age group, in 2015.[8] An additional 23,000 (15–40,000) deaths were estimated to occur in children co-infected with HIV. On average 75 percent of IPD and 83 percent of pneumococcal meningitis cases are aged under 2 years but the incidence and age distribution vary by country and socioeconomic status.[8] Importantly, at least one quarter of survivors of pneumococcal meningitis experience long-term sequalae such as hearing loss, seizures, mental and motor abnormalities.

In each geographical region globally, PCV10 and PCV13 were shown to cover more than 70 percent of the serotypes causing IPD under 5 years of age during 1980–2007 prior to PCV introduction (PCV10 range 70–94 percent and 74–88 percent for PCV13).[8]

Direct impact of PCV programmes on IPD in children

Reductions in IPD among target cohorts of children in high income countries have been similar for PCV10 and PCV7/13 in reported studies. Québec (PCV10 and 13) and Finland (PCV10) both used 2+1 schedules and observed 83 percent and 79 percent reductions in IPD in vaccine-eligible children, respectively.[9, 10] In England, using PCV7 then PCV13 in a 2+1 schedule, there was an estimated 5,000 (54 percent) fewer hospital admissions for bacteraemia, meningitis and pneumonia in children aged under 5 years over 12 years after the introduction of PCV7 and PCV13. The greatest reductions were seen in meningitis (by 71 percent) in children under 2 years age.[11]

Direct impact of vaccination on non-invasive pneumococcal disease

The impact of pneumococcal conjugate vaccination on the large burden of non‑invasive pneumococcal disease has been clearly demonstrated internationally in countries that have introduced these vaccines, particularly through reductions in childhood hospitalisations due to pneumonia.[12, 13] Other impacts, such as on acute otitis media, are less clear and more difficult to measure accurately.[14] However, a systematic review found PCVs were associated with large reductions in risk of pneumococcal acute otitis media, but there was no evidence of benefit against all‑cause otitis media in high-risk children over 1 year of age or older children with a history of respiratory illness.[15]

Herd immunity

The extent to which childhood PCV immunisation programmes provide indirect reductions in IPD among high-risk children and older adults varies between reports, settings and vaccine serotype (notably serotypes 3 and 19A). There is some good evidence for the indirect (herd) effects of infant PCV immunisation on vaccine serotype pneumococcal disease in the non-vaccinated population, especially in adults aged 65 years and older, and an all age-effect on non-bacteraemic pneumonia.[16] This includes data showing reductions in the rates of IPD due to PCV7 and, more recently, PCV13 serotypes in non-vaccinated groups in many countries (for both pneumonia and IPD in adults) in North America and Europe.[11, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26] Reductions in adult pneumococcal pneumonia have also been observed in Western Kenya following the introduction of PCV10 in children[27] and in Japanese community-dwelling older adults following the introduction of PCV13.[28] These herd effects are predominantly due to decreased nasopharyngeal carriage of vaccine types in immunised children lowering transmission to unimmunised older children and adults.

Although many countries have reported significant decreases in vaccine-type IPD among children and the wider population following the introduction of PCVs to the childhood schedules, IPD due to non-PCV serotypes has increased in some, particularly in older adults.[29, 30] Therefore, for direct protection against a broad range of serotypes 23PPV continues to be necessary for those at highest risk of IPD.

Pneumococcal disease occurs throughout the year, but is more common in the autumn and winter months.[31, 32] Incidence of IPD is highest in infants and the elderly, especially among Māori and Pacific peoples.[31, 33, 34, 35]

Isolates from cases of IPD are serotyped at ESR and detailed information by age group is regularly updated on the ESR Public Health Surveillance website.

Incidence and mortality

In 2021, there were 468 notified IPD cases and the overall notification rate was 9.2 cases per 100,000 population (ESR, 3 May 2022). The highest rates of IPD were in adults aged 85 years and older (47.5 per 100,000) and in children aged under 1 year (46.0 per 100,000), followed by adults aged 75–84 years (24.3 per 100,000) and 65–74 years (17.8 per 100,000). The age-standardised rates of IPD were highest for the Pacific peoples (31.0 per 100,000, 64 cases) and Māori (26.5 per 100,000, 149 cases) ethnic groups. These rates were 4.9 and 4.2 times higher than the age-standardised rate for the European/Other ethnic group (6.3 per 100,000, 217 cases). The incidence of IPD was 12.5-fold higher for those living in areas with the highest levels of deprivation than those living in low deprivation areas across all age groups (60.9 vs 4.9 per 100,000). IPD was recorded as the primary cause of death for 16 cases in 2022, including 5 children aged under 5 years (the most since IPD became notifiable in late 2008). In 2021, the most reported risk factor in cases aged under 5 years were children who were born premature (7.6 percent) and children who were immunocompromised (4.5 percent) (ESR, 3 May 2022).

New Zealand epidemiology since the introduction of PCV

PCV7 was introduced in June 2008, PCV10 in July 2011 and PCV13 in July 2014, PCV10 replaced PCV13 in July 2017 on the routine Schedule (see ‎Appendix 1). From October 2020, the number of primary doses of PCV10 were reduced to two (at age 6 weeks and 5 months) and the booster dose was brought forward from 15 months to 12 months. In December 2022, PCV13 replaced PCV10, given as a two-primary plus booster schedule routinely, and with an additional three-month dose of PCV13 for those with high-risk medical conditions as part of the extended immunisation programme.

IPD incidence

There have been dramatic reductions in the incidence of IPD in the vaccine-eligible age groups in New Zealand following the introduction of PCV to the Schedule in 2008 (see Figure 17.1).

In children under 2 years of age, the total rate of IPD decreased by 74.3 percent since the introduction of PCV to the Schedule in late 2008: from 46.0 per 100,000 in 2009 to 11.8 per 100,000 in 2015. However, the rate has steadily increased since 2015 and in 2021 the rate of 35.7 per 100,000 was the highest since 2009.

There has been a sustained reduction in PCV7 serotypes (see Figure ‎17.2), with few cases of PCV7 serotype IPD detected in children aged under 2 years since 2015 (ESR, 3 May 2022).

Similar reductions were seen for IPD caused by PCV10 serotypes under 2 years (see Figure ‎17.2). The incidence of all-cause IPD decreased in children aged 2–4 years from 2009 (by 45.9 percent; Figure 17.1), but have been rising again. Further, the rate of IPD due to PCV13-specific serotypes has been increasing since 2018 among children aged 2–4 years, though the rates are still lower than pre-2009 (Figure ‎17.2) (ESR, 3 May 2022). Serotype 19A has become an increasing problem, despite the theoretical cross-protection from 19F in the PCV10 vaccine.[36]

In 2021, 41.0 percent of cases in adults aged 65 years and over were PCV13 serotypes, and 73.8 percent were due to 23PPV serotypes. Of these, 37.0 percent (50/135 cases) were due to serotype 19A, and 44.4 percent were due to 23PPV-non-PCV13 serotypes (ESR, 3 May 2022).

Figure 17.1: Rate per 100,000 of invasive pneumococcal disease by age group and year, 2009–2021

Figure 17.2: Rate per 100,000 population of invasive pneumococcal disease due to PCV7 serotypes, additional PCV10 types, additional PCV13 types and non-PCV types, by age group and year, 2006–2021

There are two types of pneumococcal vaccine approved for use in New Zealand for use against S. pneumoniae: pneumococcal conjugate vaccine (PCV) with ten or 13 serotypes and a plain polysaccharide pneumococcal vaccine (PPV) containing 23 serotypes. In PCVs, the pneumococcal surface polysaccharide is coupled to a carrier protein that induces increased production of type-specific antibodies, particularly in children aged under 2 years, and immunological memory enabling booster responses with subsequent doses (see section 1.4.3). Table 17.1 presents the polysaccharide serotypes contained within each vaccine.

Table 17.1: Pneumococcal vaccine serotype content

13-valent pneumococcal conjugate vaccine

Childhood schedule

The immunogenicity of PCV13 in a 2+1 schedule (two primary plus booster) was found to be non-inferior to a PCV10 3+1 schedule (three primary doses plus booster) in Vietnam. In a clinical trial, 250 infants received PCV13 at ages 2, 4 and 9.5 months and were compared with 152 infants given PCV10 at ages 2, 3, 4 and 9.5 months or PCV10 as 2+1 schedule, and given concomitantly with DTaP-IPV-HepB/Hib. In the PCV13 group, more than 95 percent of infants responded to most serotypes after the primary doses (except for serotypes 6B and 23F). The magnitude of the response was greater for eight of the shared serotypes in the PCV13 group than the PCV10 groups. At 9 months (pre-booster), 75.4 percent to 100 percent of PCV10 groups and 68.9 percent to 99.1 percent of the PCV13 group had seroprotective antibody levels to most of the ten shared serotypes. Post-booster more than 97 percent of participants had IgG concentrations ≥0.35 µg/ml for all ten shared serotypes. Geometric mean concentrations followed a similar pattern post-booster to that seen post-primary for most serotypes. Only modest responses were seen against serotype 3 in the PCV13 group. For non-PCV10 serotypes, 94 percent of infants who received PCV13 had seroprotective levels of IgG against serotypes 3, 6A and 19A post primary and 99 percent post booster. At age 18 months, at least 95 percent of participants had seroprotective IgG levels for serotypes 14 and 19F, and for 6B (in PCV10 group), and more than 59 percent for all other shared serotypes.[43]

When breakthrough cases of IPD caused by serotype 19A were investigated in Québec, 19 of 31 cases (61 percent) occurred between ages 8 and 14 months, following two primary doses of PCV13 and prior to the toddler dose. Although PCV10-serotype 19F showed direct cross-protection against 19A in infants, there was no evidence of reduction in 19A carriage or indirect (herd) reductions in adults, whereas PCV13 did reduce 19A carriage and induce herd effects. It was proposed that a recent upswing in 19A may be due to a window of susceptibility in infants under a 2+1 schedule for PCV13 as 19A continues to circulate, but this was anticipated to decrease with stronger herd effects over time.[9]

Individuals at increased risk of IPD

Few studies have investigated the immunogenicity and effectiveness of PCV13 in individuals at increased risk of IPD. Studies using pneumococcal vaccines with similar but fewer antigens have demonstrated vaccine efficacy in individuals with immunocompromising conditions (eg, HIV, sickle cell disease), but the duration of protection against IPD remains unknown.[44] High IgG titres have been demonstrated following PCV13 vaccination of children with sickle cell disease,[45] HIV infection[46] and nephrotic syndrome.[47]

WHO recommends that children with medical conditions that reduce humoral immune response to vaccines, such as HIV, sickle cell disease and primary immune deficiencies, to have a 3+1 schedule of PCV13.[8] In children and adolescents with underlying medical conditions, such as type-1 diabetes, cancer, cystic fibrosis or asthma, the broader serotype protection provided by PCV13 can reduce nasopharyngeal carriage and the associated risk of IPD.[48, 49, 50, 51]

Use of pneumococcal conjugate vaccines in adults

PCV13 induces robust immune responses in adults,[52, 53, 54, 55] including elderly adults.[56] Although the antibody titres vary with serotype and between age groups, particularly for those aged over 65 years, the clinical significance of this variation is unclear.[53] PCV13 is at least as immunogenic as 23PPV in adults. Some studies suggest that prior 23PPV attenuates the immune response to PCV13, an effect not seen if PCV13 is given before 23PPV; conversely given first, PCV13 may augment the response to subsequent 23PPV vaccination.[56, 57, 58]

With respect to clinical outcomes, the Community-Acquired Pneumonia Immunization Trial in Adults (CAPITA) was a large, randomised, placebo-controlled trial conducted in the Netherlands that assessed efficacy of PCV13 against pneumococcal community-acquired pneumonia (CAP) with and without IPD in adults aged 65 years and older. The efficacy of PCV13 against vaccine-type IPD was 75 percent (95% CI: 41.4–90.8) and 45.6 percent (95% CI: 21.8–62.5) against vaccine-type pneumococcal CAP; 45.0 percent (95% CI: 14.2–65.3) for both combined.[59] Although this study showed individual protection for vaccine-type CAP, there was no significant reduction in all-cause pneumonia.[59]

An important uncertainty is the extent of indirect protection against vaccine-type IPD cases stemming from childhood immunisation programmes, which varies between countries. Where vaccine serotypes are sufficiently prevalent, PCV13 would provide some protection against all-cause CAP and lobular pneumonia.[60] Some of the non-PCV13 vaccine serotypes more likely to cause disease in adults are covered by 23PPV.

Data is limited for younger adults and specific at-risk adult populations.

23-valent vaccine pneumococcal polysaccharide

The polysaccharide vaccine (23PPV, Pneumovax 23) is made from the purified capsular polysaccharides of 23 serotypes of S. pneumoniae. It is available in New Zealand for adults and children from age 2 years. The 23 serotypes included in 23PPV (see Table 17.1) are responsible for about 90 percent or more of IPD in high-income countries.

See recent IPD surveillance reports from ESR for prevalence of serotypes covered by 23PPV in New Zealand (available on the Public Health Surveillance website).

A meta-analysis of IPD in adults aged from 65 years in 10 European countries showed that incidence of PCV7 serotypes had declined by 77 percent and for additional PCV13 serotypes by 38 percent after 5 years of PCV13/PCV10 immunisation programmes. The incidence rate of 23PPV-non-PCV13 serotypes had increased by around 50 percent with these 11 serotypes causing 22–54 percent of IPD.[61] In 2016, more than two-thirds of IPD cases in adults age 65 years or older were 23PPV-non-PCV13 serotypes.[40]

The efficacy of 23PPV varies depending on whether immune-competent or immunocompromised patients are studied, and whether the end point is pneumococcal pneumonia or bacteraemia.

The limitations of the polysaccharide vaccine have been summarised as:

• reduced efficacy in high-risk individuals
• uncertain efficacy against pneumonia
• it is only suitable for children aged 2 years and older.
• waning protection 2.5 to 5 years after vaccination.

A 2017 meta-analysis from Germany found pooled VE for 23PPV against any serotype IPD of 45 percent (95% CI: 15–65), 59 percent (95% CI: 35–74) or 73 percent (95% CI: 10–92) across cohort, case-control or clinical trial data; and pooled VE against any serotype pneumococcal pneumonia of 48 percent (95% CI: 25–63) and 64 percent (95% CI: 35–80) in cohort studies and clinical trials.[62] For both outcomes, waning of protection was found between 2.5 years and 5 years of follow-up after 23PPV.[62] Other systematic reviews, with differing eligibility criteria, found lower pooled VE estimates against IPD or pneumococcal pneumonia for 23PPV.[63, 64, 65] A Japanese prospective study found 23PPV to have moderate but variable effectiveness against vaccine-type pneumococcal pneumonia in adults aged 65 years or older.[66] Hence, questions remain around the clinical effectiveness and intervals between repeat doses of 23PPV that provide continued protection.

The dose of PCV13 and 23PPV is 0.5 mL, administered by intramuscular injection (see section 2.2.3). 23PPV can also be administered by subcutaneous injection (see section 2.2.3), but there is an increased likelihood of injection-site reactions.[67]

Co-administration with other vaccines

PCV13 or 23PPV may be administered at the same time as other routine childhood vaccinations, in a separate syringe at a separate injection site (see section ‎2.2.7 for information about multiple injections at the same visit).

PCV13 has been associated with increased risk of fever over 39°C and febrile convulsions when co-administered with inactivated influenza vaccine in children aged 6 months to under 5 years. Separation of the vaccines by two days can be offered but is not essential (see section ‎17.6.2). Systemic reactions have been noted in adults aged over 65 years.

Transport according to the National Standards for Vaccine Storage and Transportation for Immunisation Providers 2017 (2nd edition).

Store at +2°C to +8°C. Do not freeze.

Children aged under 5 years

PCV13 (Prevenar 13) vaccine is funded for all children aged under 5 years. Two doses of PCV13 are given as the primary course, with a booster at age 12 months (Table ‎17.2). Children who started their immunisation course with PCV10 can complete it with PCV13.

As part of the extended immunisation programme for high-risk groups, PCV13 and 23PPV are funded for eligible individuals, as shown in Table 17.3, Table 17.4 and Table 17.5. Because the recommended schedule depends on the age of the individual at diagnosis, the tables have been organised into age groups (under 5 years, 5–18 years and 18 years and older).

The PCV13 and 23PPV funding restrictions are as follows. See Table 17.3, Table 17.4 and Table 17.5 for the eligible conditions and dosing requirements.

PCV13

All high-risk infants (aged under 12 months) are recommended to receive three doses of a PCV vaccine, with at least one booster dose at or after 12 months of age. Change to the PCV13 extended schedule as soon as the infant is diagnosed as being at high risk (a dose is given at age 3 months in addition to the usual schedule).

• Two doses of PCV13 are funded for high-risk children aged from 12 months and under 18 years irrespective of previous doses of any non-PCV13 vaccine (PCV10 or PCV7); or, 
• Up to an additional four doses of PCV13 are funded for vaccination or re-vaccination of high-risk children aged under 5 years.
• Up to an additional four doses of PCV13 are funded for vaccination or re-vaccination of eligible individuals aged 5 years and older.

23PPV

• Up to three doses of 23PPV are funded for individuals with eligible conditions.
• Up to two doses of 23PPV are funded for high-risk children aged under 18 years.

Up to an additional four doses of PCV13 and up to additional three doses of 23PPV are funded for vaccination or re vaccination of high-risk individuals (as listed in Table ‎17.3, Table 17.4 and Table 17.5).

See also sections 4.2.5 and 4.6.

Risk stacking

Two classifications of IPD risk are recognised: ‘high-risk’ conditions for which there is significant risk of IPD and ‘at‑risk’ conditions, which on their own may not significantly increase risk, but when combined or with added lifestyle risk factors increase an individual’s risk of IPD. This is described as ‘risk stacking’ – IPD incidence substantially increases with the accumulation of concurrent risk factors or conditions.[3, 4] The risk of pneumococcal infections in those with two or more at-risk conditions may be as high as the risk for those with a recognised high-risk condition.[68, 69, 70]

Recommendations

PCV13 and 23PPV are recommended but not funded for the following individuals:

• immune-competent adults (aged 18 years and older) at increased risk of pneumococcal disease or its complications because of chronic illness (eg, chronic heart, renal, liver or pulmonary disease, diabetes or alcohol dependency)
• immunocompromised adults at increased risk of pneumococcal disease (eg, those with nephrotic syndrome, multiple myeloma, lymphoma and Hodgkin’s disease)
• individuals of any age who have had one episode of IPD
• smokers.

PCV13 is funded but 23PPV is also recommended and not funded for individuals with:

• intracranial shunts
• cerebrospinal fluid leakage.

For those individuals who choose to purchase PCV13 and 23PPV vaccines, providers may follow the age-appropriate schedules in Table 17.4 and Table 17.5.

Adults aged 65 years and older with no other risk factors

Give one dose of PCV13 followed at least eight weeks later with 23PPV (not funded).

Pneumococcal vaccines are not routinely recommended for pregnant women.

Women of childbearing age who are eligible for funded PCV13 and 23PPV should be vaccinated before a planned pregnancy or as soon as possible after delivery (see Table 17.5). Administration of these vaccines in pregnancy is unlikely to result in serious adverse effects and may be considered in individuals at the very high risk of IPD who were not vaccinated prior to pregnancy.[71]

PCV13 and 23PPV may be given to breastfeeding women.[71]

There are no specific contraindications to pneumococcal polysaccharide or conjugate vaccines apart from a severe reaction to a previous dose or known hypersensitivity to any components of either vaccine.

Systemic reactions (chills, rash and myalgia) may occur when PCV13 and influenza vaccine are administered at the same time. PCV13 has been associated with a slightly higher risk of fever over 39°C and febrile convulsions when co-administered with inactivated influenza vaccine in infants and young children, compared to when administered separately.[72] Febrile convulsion history is not a contraindication to PCV13 immunisation. If indicated, PCV13 and influenza vaccines may be given to a child aged under 5 years at the same visit.[71] Parents/guardians should be informed of the small risk of febrile convulsions, and separation of vaccines by two days can be offered. If the child has a history of febrile convulsions, separation of the vaccines is recommended.

23PPV should not be given to children aged under 2 years due to the reduced immune response associated with polysaccharide vaccines (see section 1.4.3).

Pneumococcal conjugate vaccines have excellent safety profiles. A 2016 systematic review found that pneumococcal conjugate vaccines are considered safe for use in children, and serious adverse events are detected very rarely by post-marketing surveillance.[73]

The most commonly reported adverse reactions after PCV13 are injection-site reactions, fever, irritability, decreased appetite and increased or decreased sleep.[74] An increase in injection-site reactions was reported in children older than 12 months compared to rates observed in infants during the primary series with PCV13.

No serious adverse events have been identified in adults or children, associated with underlying disease or immunocompromise.[75, 76, 77]

Local discomfort, erythema and induration lasting a couple of days are potential responses.[78] Local and systemic reactions, such as self-limiting mild fever, myalgia and decreased arm movement in injected limb, may occur after revaccination of adults, particularly when the second dose is given within five years of the first dose.[71]

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