http://bmj.com/cgi/content/full/324/7340/750

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Collections under which this article appears: Other respiratory medicine Drugs: immunological products and vaccines

BMJ 2002;324:750-751 ( 30 March )

Editorials

Protein conjugate pneumococcal vaccines

Offer new opportunities for high risk individuals but still lack robust evidence

Given the substantial global burden of invasive pneumococcal disease, the introduction of protein conjugate pneumococcal vaccines may provide a useful option for protecting individuals at risk. Optimism stems from a large prospective study showing that a protein conjugate pneumococcal vaccine prevented 94% of invasive disease in young children.¹ The clinical effectiveness of this vaccine now needs to be established among other children and adults at risk. These include people with increased exposure to Streptococcus pneumoniae, immunological defects due to HIV infection, bone marrow transplants, multiple myeloma, nephrotic syndrome, anatomical or functional asplenia, and older people with chronic conditions. The efficacy of the vaccine is unpredictable because the immune defects are different in each group.

The need for a strict, objective assessment of the vaccine is further enhanced by serious concerns raised recently when this vaccine was unexpectedly found to increase the rates of pneumonia in HIV infected individuals.² The lack of knowledge of the basic mechanism underlying pneumococcal vaccine failures indicates that adequate evidence should be obtained, before protein conjugate pneumococcal vaccines can be routinely recommended for people at greatest risk.

Early reports for improved protein conjugate pneumococcal vaccine immunogenicity among different target groups^3-5 have limitations in predicting clinical efficacy. Immunogenicity does not necessarily imply opsonising antibody production. One study showed that the ineffectiveness of pneumococcal polysaccharide vaccine among the elderly was due to the poor production of opsonising antibodies after vaccination regardless of antibody titres achieved.⁶ The protein conjugate pneumococcal vaccine could be a better vaccine if it could induce functionally improved immune responses. Among healthy individuals this vaccine induces a 16-300 fold increase in serum opsonophagocytic activity compared to a threefold increase induced by pneumococcal polysaccharide vaccine.⁷ Immunological memory also needs to be considered, since it may correlate with subsequent protection, even in the face of suboptimal vaccine immunogenicity. Indirect evidence for the fundamental role of memory in durable protection comes from our experience with the epidemiological impact of Haemophilus influenzae type b (Hib) vaccines. While the plain polysaccharide vaccine had no epidemiological impact, the incidence of Hib disease declined rapidly after the introduction of conjugate vaccines, and even the least immunogenic conjugate vaccines were effective. ^{8 9}

The superiority of protein conjugate pneumococcal vaccine induced immune responses is promising, but does not guarantee clinical efficacy. Prospective randomised controlled trials are indispensable. Both clinical and bacteriological outcomes should be used, acknowledging the unavoidable limitations of each endpoint. Clinical outcomes may be less specific, while bacteriological outcomes may be less sensitive in healthcare settings where few cultures are drawn or antibiotics are given before cultures are obtained. Furthermore, post implementation research is needed to document the positive effect of vaccination on nasopharyngeal carriage as well as the overall reduction in pneumococcal infections, at the community level and in risk groups. Since the vaccine is prepared by a fraction of pathogenic serotypes, an increase of invasive disease caused by virulent non-vaccine serotypes could replace that disease eliminated by vaccination. A randomised trial showed that although this vaccine decreased episodes of otitis media due to serotypes contained in the vaccine by 57%, episodes due to non-cross reactive serotypes increased by 33%.¹⁰ Thus very careful monitoring of pneumococcal disease episodes (absolute numbers and serotypes causing each episode) is necessary, after any change in strategy.

For healthcare policy makers, cost effectiveness is another important consideration. A cost benefit analysis in the United States has shown that protein conjugate pneumococcal vaccine could be cost effective among healthy infants and children.¹¹ However, the current cost is high enough and many governments in the Western world are hesitant to pay for protein conjugate pneumococcal vaccines. For developing countries, which carry the vast majority of the global burden of pneumococcal disease, the cost is prohibitive. Undernourished children worldwide are probably the group with the highest risk, and they may continue to remain outside the realm of clinical testing and use unless cost issues are resolved. Similarly, cost benefit must also be assessed in elderly and immunodeficient patients. Clinical studies should capture deaths from pneumococcal disease, overall mortality and morbidity, the use of other treatments, especially antibiotics, and the indirect implications for potential curtailment of bacterial resistance.

In the era of the global spread of multidrug resistant Streptococcus pneumoniae,¹² generating data about the efficacy of protein conjugate pneumococcal vaccine from individuals at risk is an important priority. Both the industry and health authorities should show interest in undertaking and covering the cost of randomised trials. In the United Kingdom an efficacy study among elderly people will begin soon, sponsored by the Department of Health (N French, personal communication). If efficacy of the protein conjugate pneumococcal vaccine is established and the means are found for its implementation in both developed and developing countries, the contribution to health globally could be immense. In contrast, if the protein conjugate pneumococcal vaccine fails to fulfil these expectations, other options such as peptide vaccines may need to be developed to cover the existing gaps in invasive pneumococcal disease prevention.

Vana Spoulou, infectious diseases specialist. 

Research Institure for the Study of Genetic and Malignant Disorders in Childhood and Agia Sophia Children's Hospital, Athens 11527, Greece (vspoulou@cc.uoa.gr)

Charles F Gilks, professor. 

Liverpool School of Tropical Medicine, Liverpool L3 5QA

John P A Ioannidis, chairman. 

Clinical Trials and Evidence Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece

© BMJ 2002
 

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Collections under which this article appears: Other respiratory medicine Drugs: immunological products and vaccines

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