The introduction of 23-valent pneumococcal polysaccharide vaccine for those aged 65 and over in Scotland in winter 2003/2004 was accompanied with a significantly reduced burden of invasive disease for this age group and an estimated VE comparable with results seen elsewhere [22
]. Although other studies have demonstrated the effectiveness of this intervention in reducing the incidence of IPD, high levels of chronic disease morbidity in Scotland [25
] that are not simply confined to qualifying medical conditions, meant that automatic assumptions about the likely success of such a campaign were not possible at the outset. Preliminary incidence data for winter 2004/2005, showing a continued reduced incidence of IPD in the 65+ population (equivalent annual incidence rate of 30.0/100,000 compared with 31.1 for winter 2003/2004), is further testimony to the apparent success of the programme. A marginal though inconclusive reduction in mortality risk was also suggested for IPD cases aged over 65 who had been vaccinated, although this was not statistically significant for the one winter season analysed here. The NNV to prevent one case of IPD in this evaluation (5206) is considerably lower than the recent Cochrane review estimate of 20,000 although this was calculated for a 55 years and over population where incidence would be much lower and is also based on a 50% vaccine effectiveness [10
]. Since the NNV estimates given here also used equivalent annual incidence rates after the implementation of the vaccine programme, they can be considered to be conservative.
While invasive pneumococcal disease accounts for only a small component of the morbidity from the pneumococcus, it is at the more severe end of the clinical spectrum and it is the outcome for which the evidence is strongest in showing a protective effect from 23vPPV [26
]. There is also a lack of ambiguity about a laboratory isolate, which is not the case for 'all cause pneumonia' or 'all cause mortality' which have also been used as indicator outcomes for assessing VE against pneumococcal infection [27
]. Additionally since the major rationale for the pneumococcal vaccination campaign was aimed at reducing invasive disease and its associated mortality and burden on health services, this was believed to be the most legitimate means by which to evaluate the programme's success or failure.
Observational studies can be said to assess the effects of health care interventions without influencing the care that is provided or the patients who receive it [28
]. When used in the assessment of vaccination programmes therefore they have high external validity and broad generalisability. In addition a number of randomised trials which have sought to assess the effectiveness of 23vPPV have been insufficiently powered to detect real benefits and have therefore proven inconclusive, particularly with respect to rare outcomes such as IPD [29
]. Non-randomised studies such as the current evaluation are limited by the extent to which there may be dissimilarities between vaccinated and non-vaccinated persons, in both their likelihood of receiving vaccination and in their subsequent care and follow up. Our findings that IPD patients with respiratory disease, cardiovascular disease or more than one underlying chronic health condition were no more likely to have received vaccine that those who did not, provides some reassurance in this regard. Further reassurance can be derived from the presumption that if vaccine recipients are more likely to be in poorer health, then the reported benefits in this study would be an underestimate rather than an overestimate of VE.
There are benefits as well as drawbacks to the evaluation of a pneumococcal vaccine campaign based on just a single post-implementation winter season. While the effects remain subject to between season variability according to temperature, airborne pollutants and circulating respiratory viruses [30
], the short time frame also minimises differences in effect that may arise from changes in circulating serotypes and variability in the duration of antibody response, which has been acknowledged as a problem in elderly vaccine recipients [31
]. With respect to circulating respiratory viruses, the retrospective inclusion of all four previous winter seasons benefited from known low levels of influenza (at or below seasonal baseline based on GP 'flu-spotter' consultations) in each of those seasons and during the 2003/2004 season of 23vPPV implementation [32
]. Marginal increases in influenza vaccination uptake over the study period are therefore unlikely to have influenced the disease burden of IPD. The fact that almost all vaccinated IPD patients also received influenza vaccine however means that we cannot exclude the possibility that there was some additive benefit of both vaccines as has clearly been demonstrated by other authors [33
]. The one season post-implementation study design may also yield an over-optimistic evaluation of VE that is not likely to be sustainable, due to both declining antibody levels and the increased likelihood with time of encountering non-vaccine component serotypes [35
]. Additionally, the modest scale of the Scottish population makes it feasible to centrally collate all cases of invasive pneumococcal disease allowing for completeness of reporting and comparability between different years and winter seasons. Retrospective ascertainment of vaccination status is of course less dependable than prospective clarification, but the use of GP records is more reliable than self-reporting methods [36
] as is the electronic recording of uptake rates in the sample CMR population.
In spite of our results being restricted to one winter season, it has been possible to derive VE values in those aged 65 and over that compare well with other studies that have also looked at IPD prevention [23
]. A high vaccine uptake in the first season of implementation also means that any observed effect on the burden of disease is not likely to be blurred by an annually increasing uptake rate, as has been postulated for the US [38
]. While substantial overlap between the confidence intervals makes it difficult to interpret the variation in VE by sex and age-band, the finding of the highest effectiveness being in the 75+ age category contrasts with the diminishing effectiveness with age generally seen in other studies. For the Scottish population however an element of survivor bias may be relevant, since the majority of those surviving to 75+ years of age are from higher socio-economic groups [39
]. The higher effectiveness in females aged between 65 and 74 in spite of lower vaccine uptake, may reflect higher levels of underlying chronic illness in males of this age group (although this is not evident from available risk factor data in this study, Table ). More severe underlying illness has also been linked with an increasing the likelihood of opting for vaccination [40
]. A slightly higher uptake of the pneumococcal plus flu vaccine in older males, which is a combination known to have additive benefits [33
], may also have contributed to the high effectiveness in this sub-group although, as noted previously, seasonal influenza activity was low throughout the study period. The current estimate of VE by the indirect cohort method is characterised by a high range of uncertainty although the actual value of 51% for those aged 65+ is not incompatible with a protective effect. The multiple infecting serotypes of the pneumococcal pathogen together with the high valency of 23vPPV mean that reliable estimates using this method, such as that derived by Butler in the US [41
], commonly require large numbers of cases (specifically around 2400 gathered over a period of 14 years in that particular study). Single winter season estimates such as our own or that determined in a recent Australian study [22
] inevitably have low numbers of rare non-vaccine serotypes which introduces a large margin of error.
The parallel targeting of pneumococcal vaccine with seasonal influenza has been shown to be an effective means of achieving high uptake in pneumococcal programmes for older adults [42
] and the estimated overall uptake levels in the 65+ for the season under study (at 65%) also reflect the suitability of primary care as a means of delivery. The recent Australian evaluation [22
] reported reductions in IPD incidence (36%) of similar magnitude to that seen in Scotland and VE estimates in the same range as for the current study (71%: 95%CI: 54, 82). Similarly overall VE estimates obtained from a case control study in Catalonia [23
] were also in the same range (65%: 95%CI: 35, 81). These comparisons add a measure of confidence to the generalisability of our results to other developed countries.
The inherent complexity of the pneumococcus and it's sophistication in evading the host immune response, requires that a high degree of vigilance at both the epidemiological and microbiological levels continue to accompany the ongoing implementation of this vaccine programme for older adults. A key issue in its medium to long term success will be the duration of protective effect which several studies have shown to decline rapidly in elderly subjects and in a manner that is not uniform across all serotypes [27
]. The extent to which the elderly population may have gained additional protection from the introduction of 7-valent conjugate vaccine (PCV-7) to the childhood schedule from September 2006 [13
] mediated through a herd immunity effect [43
], and as has shown promise in the US [44
], awaits further investigation. Protection against invasive disease is of course only one aspect of tackling pneumococcal morbidity and the extent to which polysaccharide vaccine, either alone or in combination with the new conjugate vaccines, might be able to reduce pneumococcal pneumonia is the next key question in tackling the societal burden of this pathogen. The evidence with regard to pneumonia is certainly less clear cut and may need to await the development of more specific and efficient diagnostic tests [45