Pneumococcal vaccines – past, present and future

Clayton Chiu
Public health physician1
Conjoint lecturer 2

Peter McIntyre
Director 1
Professor 2

1 National Centre for Immunisation Research and Surveillance for Vaccine Preventable Diseases
The Children’s Hospital at Westmead
Sydney

2 The Children’s Hospital at Westmead Clinical School
The University of Sydney

Summary

Universal vaccination of Australian children with the 7-valent pneumococcal conjugate since 2005 has substantially reduced invasive pneumococcal disease. Herd immunity has also been observed in adults.

Conjugate vaccines of higher valency, which provide additional serotype coverage, became available in 2009. The 13-valent vaccine replaced the 7-valent vaccine in the National Immunisation Program in July 2011.

The 23-valent polysaccharide vaccine is recommended for all adults aged 65 years or over and for Aboriginal and Torres Strait Islander adults aged 50 years or over. It is also indicated in younger people with risk factors for invasive disease.

Additional pneumococcal vaccine doses are recommended for children and adults at increased risk of invasive disease.

The Australian Immunisation Handbook 10th edition contains detailed recommendations.

Key words: conjugate vaccines, polysaccharide vaccination, Streptococcus pneumoniae

Aust Prescr 2013;36:88-93

Introduction

Pneumococcal vaccines are designed to prevent diseases caused by Streptococcus pneumoniae (pneumococci), broadly referred to as pneumococcal disease. There are two different types – the conjugate vaccines and a polysaccharide vaccine (Table 1). The conjugate vaccines can induce an immune memory response, and are immunogenic in young infants. In contrast, the polysaccharide vaccine is poorly immunogenic in children under two years and those with impaired immunity. Although it contains more serotypes, it is not conjugated to a protein and does not induce a memory immune response.

Among the pneumococcal conjugate vaccines, formulations vary in the number of pneumococcal serotypes included (valency) and the conjugating proteins used. Table 1 shows the serotypes contained in the pneumococcal vaccines registered in Australia. The original 7-valent conjugate vaccine has now been superseded in the National Immunisation Program by the 13-valent conjugate vaccine.

Pneumococcal disease

S. pneumoniae is a Gram-positive bacterium with a polysaccharide capsule, which is a virulence factor. More than 90 polysaccharide serotypes have been identified, with each serotype eliciting serotypespecific immune responses. Different serotypes vary in their propensity for nasopharyngeal colonisation and for causing disease. In Australia in 2002–04, before the universal infant pneumococcal conjugate vaccination program, 85% of invasive pneumococcal disease in children under two years was caused by the serotypes contained in the 7-valent conjugate vaccine (Table 1).1 Serotype distribution of pneumococcal disease is more diverse among Aboriginal and Torres Strait Islander people, including children, and among adults in general compared to children.

Transmission and carriage

Transmission of pneumococci occurs via respiratory droplets from individuals with nasopharyngeal colonisation.2 Carriage of pneumococci in the nasopharynx varies with age and environmental factors. The duration of carriage is generally longer in children. All pneumococcal disease presumably begins with nasopharyngeal colonisation.

Invasive disease and its risk factors

For disease surveillance purposes, detection of S. pneumoniae in a normally sterile site, such as blood, cerebrospinal fluid or pleural fluid, by culture or polymerase chain reaction, is classified as invasive pneumococcal disease. The highest incidence of invasive pneumococcal disease is seen among young children, especially those under two years, and in the elderly.3,4 The major categories of invasive pneumococcal disease are:

  1. meningitis, which is associated with the highest case-fatality rate and possible neurological sequelae among survivors
  2. bacteraemic pneumonia
  3. bacteraemia without focus, the commonest clinical category in young children.

Various medical, environmental and lifestyle factors are associated with an increased risk of developing invasive disease (see Box). 5,6 Aboriginal and Torres Strait Islander children and adults have a higher rate of invasive pneumococcal disease compared with other Australians.7,8

Table 1 Pneumococcal vaccines and their serotypes
Pneumococcal vaccines and their serotypes

Risk factors for invasive pneumococcal disease Ref 6

Non-invasive disease

Otitis media and pneumonia (without bacteraemia) are classified as non-invasive disease for surveillance purposes. Pneumococcus is estimated to account for over a third of all community-acquired pneumonia in adults.2

The impact of pneumococcal vaccination in Australia

In January 2005, Australia implemented universal vaccination of all young children with the 7-valent conjugate vaccine, and of adults aged 65 years and over with the 23-valent polysaccharide vaccine. Before then, there were publicly-funded pneumococcal vaccination programs for Australians with increased risks of pneumococcal disease3 (www.ncirs.edu.au/immunisation/history/Pneumococcal-history-June-2012.pdf ).

Following universal vaccination, the overall incidence rate of invasive pneumococcal disease decreased by 75% among non-indigenous children under two – from 78 per 100 000 in 2002–04 to 19.5 per 100 000 in 2007. Invasive disease caused by the seven vaccine serotypes declined by 97%, from 60.9 per 100 000 to 2.1 per 100 000.3,9 Rates of hospitalisation due to pneumonia have decreased by 38% in children under two years.10 Substantial reductions in invasive disease were also observed in older children and adults, the age groups who did not receive the vaccine. The decline was mostly due to a decrease in invasive disease caused by the seven vaccine serotypes (see Fig. 1). 3,4 This suggests a strong benefit of herd immunity, additional to any direct effect arising from the adult 23-valent vaccine program.

Increasing rates of invasive pneumococcal disease caused by serotypes not contained in the 7-valent vaccine ('serotype replacement') have been observed since 2005. Serotype 19A has emerged to become the dominant serotype causing invasive pneumococcal disease,8 constituting 44% of all invasive disease among non-indigenous children under two years of age in 2007.9 The number of cases due to serotype 19A among non-indigenous Australians increased by more than four-fold between 2002 and 2008 in most age groups.8 However, this was not seen among indigenous Australians.9,11

Notification rate for invasive pneumococcal disease caused by serotypes contained in the 7-valent pneumococcal conjugate vaccine, Australia, 2002 to 2010, by age group Ref 4

Current vaccination schedules and recommendations

In Australia, recommendations on the specific pneumococcal vaccines vary according to age, indigenous status, jurisdiction and risk of invasive disease. For more detail about the risk categories and vaccine recommendations, consult the Australian Immunisation Handbook 10th edition.6

Children

Table 2 summarises the current recommended childhood pneumococcal vaccinations. For the 13-valent conjugate vaccine, a three-dose primary vaccination schedule, at two, four and six months of age without a booster dose, is recommended. Based on efficacy data from the pivotal randomised controlled trial of the 7-valent conjugate vaccine,12 the potential additional benefits are not considered sufficient to justify a routine booster (fourth) dose for healthy non-indigenous children. For those with a higher risk of invasive disease or indigenous children living in states and territories where there is a high incidence of invasive disease (WA, NT, SA and Qld), a fourth dose of the 13-valent conjugate vaccine is now recommended ( see immunise.health.gov.au ).

Guidance on catch-up vaccination schedules for children who are delayed in presenting for pneumococcal vaccination or who have an increased risk of invasive disease, including those diagnosed after completion of the age-based recommended course, can be found in the Australian Immunisation Handbook 10th edition.6

Adults

Table 3 summarises the current recommended adult pneumococcal vaccinations in Australia. A single dose of the 23-valent polysaccharide vaccine is recommended for healthy non-indigenous adults at age 65. A routine second dose is no longer recommended, based on a harm–benefit re-evaluation in 2011.13

Younger adults with an increased risk of invasive disease, including smoking (see Box), should also be vaccinated. More doses of the 23-valent vaccine are recommended for Aboriginal and Torres Strait Islander people or those with risk factors for invasive disease. The minimum interval for a repeat dose of the 23-valent polysaccharide vaccine is five years. The maximum number of lifetime doses in adulthood is three, based on concerns regarding adverse events and limited effectiveness, and uncertainty about immune hyporesponsiveness following multiple revaccinations.

Adults with a medical condition associated with the highest increased risk of invasive disease (category A conditions in the Box) are also recommended to have a single dose of 13-valent conjugate vaccine.

Australian recommendations for pneumococcal vaccinations in children under 5 years

Australian recommendations for pneumococcal vaccinations in adults

7-valent conjugate vaccine

A pivotal US trial in a setting similar to the Australian general population found that the vaccine reduced the risk of invasive pneumococcal disease due to the seven vaccine serotypes by about 95% among infants and toddlers.12 Some cross-protection against serotype 6A invasive pneumococcal disease was also shown.14

A Cochrane review of conjugate pneumococcal vaccines reported that the pooled vaccine efficacy was 80% (95% CI 58–90%) against vaccine-type disease and 58% (95% CI 29–75%) against all serotype invasive disease in children under two years. Effectiveness against X-ray defined pneumonia was lower at 27% (95% CI 15–36%).15

Another Cochrane review on young children concluded that while the efficacy against clinically defined otitis media due to serotypes in the vaccine was about 60%, the overall preventive benefit against acute otitis media due to any cause was only 6–7%.16 This is due to the cancelling out of the preventive benefits of 7-valent vaccine against disease due to vaccine serotypes by non-vaccine serotypes and other organisms. However, studies from several countries, including Australia, have shown a decrease in the likelihood of tympanostomy tube insertion among vaccinated children.

The 7-valent vaccine is safe. However, it is more commonly associated with local adverse events and fever than comparator vaccines such as hepatitis B or meningococcal C conjugate.17 There is no pattern of increasing local reactogenicity with subsequent doses.12

Higher valency conjugate vaccines

The 10-valent and 13-valent conjugate vaccines were registered for young children based on non-inferiority of immunogenicity compared with the 7-valent vaccine. There are no definitive serological correlates of clinical protection against the whole spectrum of pneumococcal disease, especially where specific serotypes are concerned. Currently, clinical efficacy data are not available for either of these two vaccines.

10-valent vaccine (Synflorix)

This vaccine was approved in 2009 for children. While its clinical efficacy is yet to be published, a study of a prototype vaccine containing 11 pneumococcal serotypes (the 10 serotypes in the 10-valent plus serotype 3), also conjugated to H. influenzae protein D, showed significant protective efficacy against acute otitis media caused by vaccine serotypes (57.6%; 95% CI 41.4–69.3%) as well as by H. influenzae (35.6%; 95% CI 3.8–57.0%).18

The safety profile of the 10-valent vaccine is similar to that of the 7-valent vaccine, with no clinically relevant difference when co-administered with routine childhood vaccines.19

There are no specific data available that address the immunogenicity and safety around the interchangeability of the 10-valent vaccine and other CRM 197 -conjugated vaccines (see Table 1). However, a mixed schedule consisting of different conjugate vaccines necessitated by changes in vaccination programs is considered acceptable.

13-valent vaccine (Prevenar 13)

Children

This vaccine was approved in 2010 for children. Because of the extensive postmarketing data on the 7-valent vaccine, and established immunologic correlates of protection against invasive pneumococcal disease in children, efficacy trials have not been conducted.20 Licensing in Australia has been based on non-inferiority of immunogenicity for the 7-valent conjugate vaccine serotypes and comparable antibody responses to the additional serotypes. This includes serotype 19A, which has emerged as the dominant serotype in Australia. Field effectiveness against invasive pneumococcal disease caused by the additional serotypes contained in 13-valent vaccine has been shown.21

The safety profile of the 13-valent vaccine is similar to that of the 7-valent vaccine.22 However, post-licensure surveillance in the USA has suggested that there is a slightly higher risk of febrile seizures in young children within a day of concurrent administration with inactivated trivalent influenza vaccine compared with the vaccines given alone on separate days (especially in children aged 12–23 months).23 Concurrent administration of these two vaccines is considered acceptable. However, if relevant, parents should be given the option of having the vaccines separately at least three days apart.6

Adults

In 2011, the 13-valent vaccine was registered in Australia for adults aged 50 years and over, based on immunogenicity data showing comparable or better antibody responses compared to the 23-valent polysaccharide vaccine for the shared vaccine serotypes.

There is only limited safety information on the 13-valent conjugate vaccine in adults. Pain, redness and swelling at the injection site is observed in about half of vaccine recipients. Concurrent administration of trivalent inactivated seasonal influenza vaccine with the 13-valent vaccine may increase the frequency of systemic but not local reactions.24

23-valent polysaccharide vaccine (Pneumovax 23)

This vaccine is available for adults and children two years and over. The majority of serotypes found in invasive pneumococcal disease isolates of Australian adults are contained in this vaccine.25,26

A Cochrane review in 2013 estimated that pneumococcal polysaccharide vaccines have an overall protective efficacy of 74% (95% CI 55–86%) against invasive disease in adults.27 Recent observational data from England and Wales have shown moderate effectiveness (48%) of the 23-valent vaccine against invasive disease within two years of vaccination in adults aged 65 years or over. However, effectiveness waned after two years and became insignificant after five years. In the subgroup of adults aged 65–74 years who had no clinical risk factors for pneumococcal disease, effectiveness was higher (65%) and was maintained for longer.28 There are no specific studies on the clinical effectiveness of a second dose of the polysaccharide vaccine.

Boosting of antibody responses to the 7-valent vaccine serotypes after vaccination with the polysaccharide vaccine has been shown in small studies of children and adults with underlying medical conditions. Some antibody response to a few additional polysaccharide vaccine serotypes was also observed.

The frequency of adverse reactions varies among study populations (and possibly with age), and is higher with repeat doses. At least half of the recipients will experience some soreness at the injection site after the first dose. Swelling and redness are also very common (approximately 20%). More severe injection site reactions occur in up to 5% of first dose recipients and may occur in up to 20% of people after a second dose.29–31 In these studies, repeat doses were given at least five years after the previous dose. Cellulitis-like reactions can also occur. Local adverse events occurred more often after subcutaneous administration than after intramuscular administration.32 Systemic reactions like myalgia, fatigue and chills are also very common.

Conclusion

The universal childhood pneumococcal conjugate vaccination program has substantially reduced pneumococcal disease, especially invasive disease in the target age group. Herd immunity has been observed in other age groups. Introduction of the 13-valent vaccine is likely to lead to further reduction in invasive pneumococcal disease caused by emergent serotypes, particularly 19A.

The 23-valent polysaccharide vaccine is modestly effective against invasive pneumococcal disease in adults, including older adults, especially those without underlying chronic medical conditions. However, due to an increase in local reactions after repeat doses, revaccination should be limited to those with higher risks of invasive pneumococcal disease.

References

Conflict of interest: none declared

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  11. Lehmann D, Willis J, Moore HC, Giele C, Murphy D, Keil AD, et al. The changing epidemiology of invasive pneumococcal disease in Aboriginal and non-Aboriginal Western Australians from 1997 through 2007 and emergence of nonvaccine serotypes. Clin Infect Dis 2010;50:1477-86.
  12. Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-95.
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  15. Lucero MG, Dulalia VE, Nillos LT, Williams G, Parreño RA, Nohynek H, et al. Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and X-ray defined pneumonia in children less than two years of age. Cochrane Database Syst Rev 2009;4:CD004977.
  16. Jansen AG, Hak E, Veenhoven RH, Damoiseaux RA, Schilder AG, Sanders EA. Pneumococcal conjugate vaccines for preventing otitis media. Cochrane Database Syst Rev 2009;2:CD001480.
  17. Destefano F, Pfeifer D, Nohynek H. Safety profile of pneumococcal conjugate vaccines: systematic review of pre-and post-licensure data. Bull World Health Organ 2008;86:373-80.
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  29. Hammitt LL, Bulkow LR, Singleton RJ, Nuorti JP, Hummel KB, Miernyk KM, et al. Repeat revaccination with 23-valent pneumococcal polysaccharide vaccine among adults aged 55–74 years living in Alaska: no evidence of hyporesponsiveness. Vaccine 2011;29:2287-95.
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  31. Musher DM, Manoff SB, Liss C, McFetridge RD, Marchese RD, Bushnell B, et al. Safety and antibody response, including antibody persistence for 5 years, after primary vaccination or revaccination with pneumococcal polysaccharide vaccine in middle-aged and older adults. J Infect Dis 2010;201:516-24.
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Further Reading

Vaccines and immunisation. NPS better choices, better health. 2012 Nov.
www.nps.org.au/medicines/immune-system/vaccines-and-immunisation

Immunise Australia website (includes the latest edition of the Australian Immunisation Handbook)
immunise.health.gov.au

Centers for Disease Control and Prevention. Pneumococcal disease. In: Epidemiology and prevention of vaccine-preventable diseases. The pink book: course textbook. 12th ed. 2012.
www.cdc.gov/vaccines/pubs/pinkbook/downloads/pneumo.pdf

UK Department of Health. Immunisation against infectious disease: the green book. 2013 Mar.
https://www.gov.uk/government/publications/green-book-the-complete-current edition

Self-test questions

The following statements are either true or false (click here for the answers)

1. A fourth booster dose of the 13-valent conjugate pneumococcal vaccine is not recommended for non-indigenous healthy children.

2. The 23-valent polysaccharide vaccine is recommended for all Aboriginal and Torres Strait Islander people aged 50 or older.



First published online: 26th of May 2013