Review
Combined schedules of pneumococcal conjugate and polysaccharide vaccines: is hyporesponsiveness an issue?

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Summary

Streptococcus pneumoniae is a major cause of morbidity and mortality in children less than 5 years of age. Prevention of pneumococcal disease and death in children in the developing world through vaccination with recently developed, highly efficacious pneumococcal conjugate vaccines (PCVs) is now possible. Schedules combining PCV with 23-valent pneumococcal polysaccharide vaccine (PPV23) have been studied and proposed as a means to expand disease protection against serotypes not included in the PCVs. Studies of group A and C meningococcal polysaccharide vaccine and repeated doses of PPV23 in adults and children have shown that a state of immune tolerance, or hyporesponsiveness, can develop to repeated polysaccharide vaccine antigen exposures. In this Review, we describe the evidence for and against this hyporesponsiveness and explore the possible mechanisms for such an occurrence.

Introduction

Vaccination of infants and young children against pneumococcal disease has become a global health priority (figure). WHO estimates that every year up to 1 million children under 5 years of age die from pneumococcal disease, making it the most important cause of vaccine-preventable deaths in this age-group. An increase in the awareness of the pneumococcal disease burden, through improvements in laboratory and clinical surveillance methods, has coincided with the availability of highly efficacious pneumococcal polysaccharide-protein conjugate vaccines (PCV). Pneumococcal polysaccharides are T-cell independent antigens that are poorly immunogenic for important pneumococcal serotypes in infancy. The conjugation of pneumococcal capsular polysaccharide to carrier proteins results in a T-cell dependent immune response, characterised by increased antibody concentrations in infants, induction of memory cells, and a booster response upon subsequent antigenic exposures.1, 2, 3, 4 This same concept led to the development of conjugate vaccines for Haemophilus influenzae type b (Hib); widespread use of these vaccines led to a more than 90% decline in invasive Hib disease in children in the USA5 and in other countries where the vaccines have been implemented.

In February, 2000, the first PCV, PnCRM7 (Prevnar, Wyeth Vaccines, Pearl River, NY, USA), was licensed in the USA and recommended for routine use in children younger than 2 years of age.6, 7 The vaccine contains polysaccharides or oligosaccharides to seven pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, 23F), each conjugated to non-toxic diphtheria toxin material, CRM197. Four large clinical trials of the seven-valent or closely related nine-valent PCV in the USA, South Africa, and The Gambia have reported vaccine efficacy between 77% and 97% for serious invasive pneumococcal disease caused by vaccine serotypes.8, 9, 10, 11 PCV efficacy against radiologically confirmed pneumonia has ranged from 19% to 37%.9, 10, 11, 12 The Gambian trial was able to assess the effect of PCV on mortality; there was a 16% reduction in all-cause mortality in children 3–29 months of age who received PCV compared with those who had not received the vaccine.11 Since these trials were done with vaccines against only seven or nine pneumococcal serotypes, there are opportunities for an even greater vaccine effect with the eventual licensing and use of higher valency PCVs.

With the opportunity for pneumococcal disease prevention in the developing world on the near horizon, there is increasing attention on optimising vaccine schedules, introduction strategies (ie, catch-up or no catch-up), and products or combinations of products for maximum public-health impact. Different vaccine regimens, such as reducing the number of PCV doses or combining sequential doses of PCV and pneumococcal polysaccharide vaccine (PPV), are being considered by some decision makers. Combined PCV/PPV regimens have the theoretical possibility of broadening serotype coverage and they might also reduce the cost of vaccination. Pneumococcal vaccine strategy decisions should consider the proportionate and absolute serotype coverage, optimum immunological protection in vaccinated individuals, and the immunological pressure in the community.

The 23-valent pneumococcal polysaccharide vaccine (PPV23), licensed for use in adults and children more than 2 years of age in the USA since 1983 and in several other countries since then, was developed for the prevention of adult invasive pneumococcal disease and pneumonia. One dose contains 25 μg of each of the 23 serotypes; the dose was selected for the preceding PPV14 product following dose-ranging studies of 10, 25, and 50 μg per serotype.13 PPV23 use has been limited in infants and young children because the T-cell independent immune response induced by PPV23 is poorly developed in young children. However, an evaluation of PPV efficacy in infants and young children in Papua New Guinea, a country with one of the highest documented rates of childhood pneumococcal disease, was done in the early and mid-1980s.14 In this study, PPV14 or PPV23 was given to children 6–59 months of age; children who were 6–17 months of age at vaccination received a second dose 12 months after their first dose. A 50% reduction in acute lower respiratory tract mortality was reported in children vaccinated before 2 years of age. Mortality from all-causes was 19% less in the vaccinated group.14

Other studies have failed to show efficacy of PPV against invasive disease or against otitis media in children.15, 16 On the basis of these and other findings, PPV23 has not been recommended for routine use in children younger than 2 years of age.

With the registration of PnCRM7, some health authorities have considered or recommended a combined schedule of PCV/PPV for some populations (eg, Australian aboriginal populations, some Native American populations, children with HIV or sickle-cell disease). A systematic review of the evidence on which such programmatic decisions could be based has not been published. An important consideration is the immunological effects of combined PCV/PPV schedules. In this Review, we aim to assess these immunological issues.

Section snippets

Immunogenicity of PPV23 or PCV boost following PCV

PPV23 vaccine has been used in combination with various PCVs in preregistration studies to evaluate the priming nature of PCV. Studies with PCV/PPV23-combined regimens have also been done in patient populations for whom PPV23 is routinely recommended (eg, elderly people, individuals with sickle-cell disease or HIV infection). All such studies have been done using the PPV23 dose that is licensed for administration to adults (ie, 0·5 mL of vaccine containing 25 μg of each antigen).

Studies

Basis of concern for hyporesponsiveness with PPV23

As discussed above, PPV23 as a booster dose following a priming series of PCV induces higher concentrations of antibodies than a PCV booster. Beyond the concerns of antibody quality and programmatic issues is the concern that use of PPV23 in infants might induce immunological hyporesponsiveness to subsequent pneumococcal antigenic exposure.

Studies have shown that repeated doses of bacterial polysaccharides might induce a state of immune tolerance, or hyporesponsiveness, to these vaccine

Postulated mechanisms of hyporesponsiveness from PPV23 and supporting in-vitro evidence

The data summarised here are mostly observational data of reduced or impaired antibody responses following exposure of children or adults to multiple doses of PPV23. There are several mechanisms by which such an exposure could lead to a adverse immune response, but the mechanism by which large doses of pneumococcal polysaccharides, as found in PPV23, might induce subsequent hyporesponsiveness is unclear.

When added in large amounts in vitro, polysaccharides may be able to downregulate B cells.70

Conclusion

Studies evaluating multiple doses of vaccines containing polysaccharide from various bacteria have shown an altered immune response to subsequent polysaccharide challenge. It is not clear from the efficacy data of human vaccine regimens whether these observations have important clinical implications and if so, to what degree any hyporesponsiveness might affect clinical disease prevention.

Studies appropriately designed to directly address whether hyporesponsiveness occurs following full-dose

Search strategy and selection criteria

We searched PubMed for relevant studies published from 1995, to March, 2006. Additional studies were retrieved by review of references from relevant articles and the authors' files. Search terms were “pneumococcal conjugate vaccine”, “pneumococcal polysaccharide vaccine”, and “invasive pneumococcal disease”. We reviewed abstracts from the International Symposium on Pneumococci and Pneumococcal Diseases (1998–2006) and from the Interscience Conference on Antimicrobial Agents and

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