Raising the profile of pneumococcal disease

Diseases caused by Streptococcus pneumoniae (the pneumococcus) are familiar to most health professionals. This high-grade pathogen is the most important cause of pneumonia in all age groups throughout the world and is one of the most important causes of meningitis, otitis media and bacteraemia. The global burden of pneumococcal disease is enormous. Although it is difficult to obtain precise incidence data because of the limited availability and performance of diagnostic tests,1 conservative estimates place pneumococcal disease among the world’s higher-profile major infectious diseases, such as tuberculosis, malaria and HIV infection. Each year, pneumococcal disease is estimated to kill approximately 1.6 million people, including up to 1 million children less than 5 years old.2 Pneumococcal disease is probably the world’s single biggest killer of young children. Updated estimates of disease burden will be released later this year with the publication of the findings of the World Health Organization’s global burden of pneumococcal and Haemophilus influenzae type b disease project. Yet, few such major diseases have such a low public profile. This situation is changing, largely because of the publicity surrounding the recently available pneumococcal conjugate vaccine (PCV). Vaccines against pneumococcal disease are not new. The first pneumococcal vaccine to become widely available was the polysaccharide vaccine (PPV), which was first licensed in the 1970s and is now mainly marketed as a 23-valent preparation (i.e. it contains 23 pneumococcal serotypes commonly associated with invasive disease). Although offering protection against invasive pneumococcal disease in adults, PPV is poorly immunogenic in children <2 years of age and has no booster antibody response on revaccination. Consequently, it has been largely reserved for people ≥65 years of age and for other high-risk individuals. Even in adults, the efficacy and effectiveness of the PPV is debated, although the collective evidence from randomized controlled trials and observational studies support an effect of the vaccine against pneumococcal pneumonia in immunocompetent adults.3 The evidence is less strong for adults immunocompromised because of malignancy, organ transplant or immunosuppressive medications. Furthermore, PPV has limited ability to reduce mucosal carriage of pneumococcus and therefore provides minimal protection against mucosal pneumococcal infection.4,5 Conjugation of the pneumococcal capsular polysaccharide to a protein carrier converts it to a T-cell-dependent antigen and the PCV establishes a state of immunological priming and memory.6 This results in substantial enhancement of antibody responses on boosting. Importantly, PCV elicits good functional antibody responses in infants and young children and this has been translated into vaccine efficacy. To date, four randomized controlled trials have shown the efficacy of PCV against culture-confirmed invasive pneumococcal disease in young children.7–10 Although these trials had important differences in geographic location (two in the USA, one each in The Gambia and South Africa), study design (three individually randomized, one cluster randomized), vaccine preparation (7-valent and 9-valent) and HIV prevalence of the study population (high in the South African site), efficacy was high in all studies. Vaccine efficacy against culture-confirmed invasive pneumococcal disease caused by the seven common pneumococcal serotypes present in all vaccines among HIV-negative children ranged between 77 and 97%.7–10 For HIV-positive children from South Africa, the efficacy of PCV was 65%.9 In the Gambian trial, vaccine efficacy against radiographically proven pneumonia was 37% and against all-cause mortality was 16%.8 A sharp decline in vaccine-serotype invasive pneumococcal disease has been noted in the USA since the 7-valent PCV was included in the routine vaccination schedule of infants in 200011,12 and epidemiological studies have shown the vaccine to be highly effective in practice with effects similar to the clinical trials.13,14 Data on the efficacy and effectiveness of PCV against pneumococcal disease in adults are still emerging, with several ongoing trials, although it is anticipated that it will perform better than PPV in this age group.15 Regardless, the effect of PCV on adult disease is already being felt in countries that have introduced PCV into their routine childhood vaccination programmes. Since the introduction of PCV into the routine schedules in the USA in 2000 and Canada in 2002, there has been a significant reduction in invasive pneumococcal disease among individuals who were not vaccinated.11,12,16–19 In the USA, most of the absolute rate reduction occurred in those aged ≥65 years, with rates of invasive pneumococcal disease caused by vaccine serotypes decreasing by 65% and rates of total invasive pneumococcal disease decreasing by 31% in this age group from 1998–1999 to 2003.19 This indirect or herd effect has presumably occurred through reduction in nasopharyngeal colonization and transmission of vaccine-type pneumococci from vaccinated children. The unexpected magnitude of the indirect effect of PCV further improved the vaccine’s economic analysis as a cost-effective intervention.20 Widespread use of PCV may also have an effect on antibiotic-resistant pneumococci.6 In many parts of the world, serotypes included in PCV cause most diseases due to resistant strains. Vaccine-induced changes in pneumococcal carriage in the nasopharynx may reduce the opportunity for vaccine strains to be exposed to antibiotics and for resistant strains to be transmitted to older children and adults. Reduction in rates of antibiotic-resistant strains of pneumococcus has already been recorded in the USA since the introduction of PCV.11,21 The inclusion of large numbers of different pneumococcal polysaccharides in a conjugate vaccine is technically challenging. Consequently, current conjugate vaccines can only protect against a limited number of the 90 pneumococcal serotypes. Although vaccines are designed to include the common serotypes responsible for most cases of invasive pneumococcal disease, geographic variation in serotype distribution can possibly influence the effectiveness of PCV. Also, there is a risk of an increase in disease caused by non-vaccine serotypes in the wake of a reduction in vaccine-type disease – the so-called replacement disease. Carriage studies suggest that this replacement phenomenon will probably occur6 and the important question is whether the replacement serotypes will cause disease as severe as the serotypes they replace. Early reports have indicated that replacement disease may be occurring in regions where the PCV has been introduced.22–24 However, the magnitude of this increase is small and it is difficult to assess how much of the increasing incidence of invasive pneumococcal disease caused by non-vaccine serotypes is directly attributable to the vaccine. Careful ongoing surveillance in populations where PCV is introduced is clearly warranted and long-term follow up will provide a better understanding of the replacement phenomenon. Vaccine development is continuing and the only PCV currently on the market (the 7-valent vaccine produced by Wyeth) will soon be joined by other formulations that should further improve vaccine effectiveness. The vaccines closest to licensure are a 13-valent vaccine produced by Wyeth (an expanded version of the 7-valent vaccine also containing serotypes 1, 3, 5, 6A, 7F and 19A) and a 10-valent vaccine conjugated to protein D from H. influenzae developed by GlaxoSmithKline. The latter vaccine is likely to provide protection against non-typeable H. influenzae disease as well as against pneumococcal disease. Development of pneumococcal protein vaccines is also ongoing. At the time of writing, 24 countries (including Australia) have introduced PCV into their childhood vaccination programmes and several other countries (including New Zealand) will be doing so very soon. With the greatest burden of pneumococcal disease being in developing countries, activities to provide innovative funding mechanisms and to heighten awareness are needed to facilitate the introduction of PCV into areas that most need it. The establishment of the advanced market commitments (AMC) initiative (www.vaccineamc.org) has brought the accelerated introduction of PCV closer to reality. AMC is an innovative funding concept whereby there is a financial commitment by donors to subsidize vaccine purchase at a set price if it meets specified criteria and is demanded by developing countries. The AMC provides assurances of a future price as incentive for more timely investment by industry, provides predictability of long-term price and future financing for countries and only uses funds if suitable vaccines are developed. PCV is being used as a pilot AMC and is predicted to have a long-term impact of preventing 5.4 million child deaths. There is also a need to raise awareness and advocate for prevention through vaccination of pneumococcal disease among governments, international institutions, officials in philanthropy and other leaders in health. The Pneumococcal Awareness Council of Experts (PACE), a working group of health experts convened by the Sabin Vaccine Institute, was recently established with this purpose (www.sabin.org/pace). An important activity of PACE is a Global Call to Action involving the support of professional societies from around the world to call on various stakeholders to work together to ensure that safe, effective pneumococcal vaccines are made widely available at affordable and sustainable prices. The PCV has provided a wonderful opportunity to reduce the burden of one of the world’s major infectious diseases. However, new pneumococcal vaccines should be viewed in the context of pneumonia and meningitis in general. For children in particular, pneumonia is a forgotten killer25 and, with vaccines for H. influenzae type b and measles, improvements in environment and nutrition, and case management standards, we now have several strategies to prevent this disease.

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