In the Western world pneumococcal vaccine is almost universally recommended for adults who are at high risk for infections caused by Streptococcus pneumoniae
because of an immuno-compromised state or certain diseases. Furthermore, in many of the nine countries in which it is used it is recommended for all elderly persons. This is in spite of the fact that most recent publications allow that "results of published controlled trials of pneumococcal vaccination in people with risk factors for pneumococcal infection are unclear" [7
]. Several, but not all, retrospective studies suggest that it may be effective in preventing invasive pneumococcal disease, at least in immunocompetent people. In 1994 the results of prospective randomised trials suggested the lack of efficacy in most Western populations [4
]. Despite this, another systematic review [5
] using randomised and quasi-randomised studies, and making no distinction as to types of patients likely to be vaccinated in Western populations, concluded that pneumococcal vaccination was effective. Even so, 2520 older people would need to be vaccinated to prevent one case of bacteraemia at one year [5
]. In their sensitivity analysis, excluding studies both quasi-randomised and unblinded studies, statistical significance was lost.
Three additional trials [21
] have been published since 1996 (the date of the last search of the most recent review was November 1996 [5
]), and we have included two studies missed by the previous review [19
]. Improper randomisation has been shown consistently to lead to bias [28
]. We chose not to include three large studies, both old [24
] and new [26
], that were quasi randomised. The two quasi-randomised studies from the 1930s and 1940s (26,000 patients) concluded the vaccine was effective. A recent quasi-randomised study in 27,000 over 65s in Finland found pneumococcal vaccination ineffective.
Though it is alleged that the vaccine is inexpensive, the cost to the NHS in England in 1999 was still a minimum of £5.4 million in prescription cost alone [31
]. Additional expense, time and effort are required to implement vaccination policies. Obviously these costs would increase with expanded use of the vaccine. Much emphasis has been placed on the possible beneficial effects of pneumococcal vaccines in reducing pneumococcal bacteraemia. This is a rare event, occurring in about 7/100,000 of the general population [32
]. Yet the data from prospective trials in high-risk patients show no statistically significant decrease in pneumococcal bacteraemia in vaccinated patients (0.8% versus 1.4%).
The modern pneumococcal vaccine has now been licensed for two decades, yet the debate over its efficacy persists [1
]. Part of the reason for the controversy is that the current vaccines were not subjected to randomised controlled trials before their release. It is therefore crucial, despite assertions to the contrary [33
] that the new protein-conjugated pneumococcal vaccines are properly evaluated.
Some advocates of the vaccine argue that logistical difficulties, great expense, and ethical concerns make randomised trials unsuitable for resolving the pneumococcal vaccine controversy [34
]. They suggest that properly conducted non-experimental studies offer attractive alternative strategies. But all observational designs are weakened by their reliance on allocation of vaccine by physician and patient preference. They also suffer from the potential for prognostic susceptibility bias, including inequalities of unknown risk factors, and the degree of reliability and availability of information on risk factors. Other sources of bias include those related to exposure-ascertainment, migration, and detection. Furthermore, all non-RCT designs require analytic assumptions to translate results into estimates of protective efficacy. The change from statistically significant results for pneumococcal vaccines when quasi-randomised trials were excluded [5
] and the controversy over mammography trials [30
] are reasons enough why properly conducted randomised trials are needed.
Even advocates of the pneumococcal vaccine agree, however, that randomised controlled trials are the most powerful design for preventing bias and estimating protection by the vaccine directly, without the need for assumptions [34
]. They contend that the prospective controlled trials have been "inconclusive," and that failure to demonstrate efficacy should not be taken as evidence that the vaccine lacks efficacy [2
]. There have been 13 RCTs of the multivalent pneumococcal vaccine, and the meta-analysis technique affords a means of combining the data on the 45,295 subjects enrolled in these studies. Our analysis of the available randomised suggests that the trials should be divided by the type of patients enrolled. Three studies have shown that the vaccine is effective (with low numbers needed to treat) in unique populations of healthy young adults at high risk for pneumococcal infection, such as South African gold miners and New Guinea highlanders. These subjects are capable of mounting a vigorous antibody response to the polysaccharide vaccine. They are also exposed to respiratory irritants (mining dust or fireplace smoke), which increases the risk of developing pneumonia. Finally, they share close living and sleeping quarters, which enables easy spread of a virulent strain of Streptococcus pneumoniae
in the community [35
]. This set of unusual circumstances is ideal for demonstrating the potential efficacy of the pneumococcal vaccine. Most pneumococcal infections are, however, sporadic; outbreaks in the antibiotic era caused by a single serotype are rare [36
In more commonly encountered circumstances the vaccine is not effective. Adults with immunosuppressing conditions, and many with chronic medical disorders, are unable to mount an adequate antibody response to the vaccine [7
]. Antibody response and vaccine efficacy are also reduced in the elderly [37
],especially after age 75 [38
], and wane more quickly [39
]. Furthermore, since pneumonia in the elderly is usually caused by aspiration of oropharyngeal secretions, pneumococcal vaccine may prevent infection with S. pneumoniae
but not pneumonia of other causes. Thus in non-epidemic situations the vaccine may be less effective in preventing pneumococcal infections. Even if the vaccine were effective, vaccinating millions of people in the UK in the hope of preventing perhaps 60% of the 7 cases of pneumococcal bacteraemia/100,000 [32
] persons is of dubious value.
In the absence of strong data supporting the efficacy of pneumococcal vaccine, advocates have based their recommendations on the fact that the vaccine is relatively inexpensive and safe. Vaccination routinely causes discomfort at the injection site for a few days, and in perhaps 5-10% of patients this may be sufficient to interfere with daily activities [40
]. The results of several of the RCTs, especially that in HIV-infected Ugandans [23
] suggest that the vaccine may in fact have adverse effects. If all of the elderly persons and patients with various chronic medical conditions and immunosuppressing diseases that are targeted were to be vaccinated, the aggregate financial and administrative costs would be great. Moreover, since vaccine protection is thought to last only about five years (and perhaps 2-3 years in patients at highest risk), re-immunisation would be necessary for most recipients [35
]. This has lead some to recommend monitoring vaccinees' antibody response a few weeks after administration, and annually thereafter, to ensure adequate response and to determine the appropriate time for revaccination [35
]. This would greatly add to the cost of a vaccination program, and any potential benefits would have to be balanced against the known harm of vaccination and revaccination [40
In the end it comes down to this: prospective randomised trials in the types of patients targeted in the Western world show the vaccines to be ineffective while retrospective studies show that it may be effective. If ten studies involving over 24,000 high-risk individuals fail to show any benefits, then programmes for mass pneumococcal vaccination need to be re-thought.