Failure to vaccinate or failure of vaccine? Effectiveness of the 23-valent pneumococcal polysaccharide vaccine program in Indigenous adults in the Northern Territory of Australia

doi:10.1016/j.vaccine.2009.12.066

Vaccine

Volume 28, Issue 11, 8 March 2010, Pages 2296-2301

https://doi.org/10.1016/j.vaccine.2009.12.066 Get rights and content

Abstract

Over the last decade, there has been no discernible reduction in Invasive Pneumococcal Disease (IPD) amongst Indigenous adults in the Northern Territory (NT) of Australia, despite increasing vaccination coverage. We examined the utility of two common methods, the screening method and the indirect method, to determine the 23-valent pneumococcal polysaccharide vaccine effectiveness (VE) in prevention of IPD amongst Indigenous adults in this setting. VE was calculated for the period 2001–2005 across two distinct geographical areas where the disease burden was known to differ. VE against vaccine-type IPD was 3.4% (95% CI −43, 35) for the NT. However, population vaccination coverage varied widely according to geographical region and where this was within the range appropriate for the use of the screening method, VE was within the expected range (67.2%, 95% CI 47, 80). VE according to the indirect cohort appeared unreliable in this setting due to the analysis being based on a very limited number of non-vaccine-type IPD cases. Surveillance based estimates of VE such as these need to be considered with caution, but the results suggest failure to vaccinate is the most likely reason vaccine-type IPD has not reduced in this setting.

Introduction

In common with other economically developed countries, age-specific rates of Invasive Pneumococcal Disease (IPD) in Australia are highest in the very young and the elderly. There is a marked disparity for Indigenous Australian adults residing in the Central region of the Northern Territory (NT), first recognised more than a decade ago [1], where age-specific rates for Indigenous adults aged 20–49 years were over 20 times those of their non-Indigenous counterparts—178/100,000 population (95% CI 132–235) compared to 8/100,000 (95% CI 3–16).

Indigenous Australians experience high rates of conditions that have not only been associated with increased risk of IPD, but also with reduced vaccine effectiveness (VE). Such conditions include high rates of alcohol abuse and associated malnutrition, smoking, diabetes mellitus, chronic renal failure and cardiac disease [2].

In light of this high disease burden, since 1995 the 23-valent pneumococcal polysaccharide vaccine (23vPPV) has been recommended for all Indigenous Australian adults aged ≥50 years and for those aged 15–49 years with medical risk factors [3]. As a regional initiative, this was expanded in 2000 to include all Indigenous adults in the NT aged ≥15 years [4]. Re-vaccination was recommended every 5 years, but since 2003, a maximum of three lifetime doses is now recommended for Indigenous adults—a second dose 5 years after the first dose and then a third dose 10 years after the second, or at age 50 years, whichever is later [3].

Data on the effectiveness of pneumococcal polysaccharide vaccine continues to remain controversial [5], [6], [7], [8]. A Cochrane Review [5] provided supportive evidence for the prevention of IPD in adults with a pooled odds ratio (OR) from randomised controlled trials of 0.26 (95% CI 0.15–0.46), supported by pooled data from non-randomised studies (OR 0.48 95% CI 0.37–0.61). The protective value of vaccination in adults with chronic illness was less clear, with data from randomised controlled trials failing to demonstrate protective efficacy for this group [5], [9]. Although this may be due to inadequate sample size and lack of power, it is of concern given that adults with chronic illness are a primary target for vaccination. A subsequent review has raised further questions about the quality of clinical trials and has led to calls for withdrawal of recommendations for the use of 23vPPV in high risk groups [6], [10].

Within the NT, surveillance of IPD has been conducted since 1994 with laboratories required to report all cases to the NT public health authority. As the only licensed vaccine for adolescents and adults, the 23vPPV is the current standard for IPD prevention in these ages. Monitoring vaccine effectiveness in the field is essential, particularly so in the NT where there is high lifetime exposure to pneumococci [11], increased susceptibility to disease, repeated vaccination and the continued high burden of IPD amongst Indigenous adults. We aimed to describe IPD incidence over time and determine the effectiveness of the 23vPPV in this population group.

Section snippets

Enhanced surveillance

IPD was defined as a pneumococcal infection with Streptococcus pneumoniae isolated from a usually sterile body fluid. Cases occurring between 1 January 1994 and 31 December 2005 were identified from the NT notifiable diseases database. Enhanced surveillance for each notified case was conducted routinely by the NT public health authority. Enhanced surveillance included medical record review, search of the regional immunisation database and patient interview (where possible) to collect clinical

Results

From 1994 to 2005, there were 444 IPD cases aged 15–49 years, 87% of whom were Indigenous (Table 1). Rates of IPD amongst Indigenous adults in the NT were 110 per 100,000 population over this period, 18 times that of non-Indigenous adults. Indigenous adults in the Central region were four times more likely to develop IPD (222/100,000) than their counterparts residing in the Top End (56/100,000).

Of the 385 IPD cases in Indigenous adults, a serotype was available for 342 (89%). Of these cases,

Discussion

Results presented in this paper indicate that rates of IPD in Indigenous Australian adults in the Northern Territory have remained constant despite increasing vaccination coverage. Whilst these data suggest the vaccine program has not had any significant impact on IPD prevention, the primary reason for this appears to be poor uptake of the vaccine rather than poor performance of the vaccine. Our analysis highlights the limitations of two commonly used methods for assessing vaccine effectiveness

Conclusions

Our data suggest that a failure to vaccinate may be the root issue that accounts for the failure to observe a reduction in IPD in our setting. Although we welcome the development of new vaccines, the current formulations of low valency pneumococcal conjugate vaccines are unlikely to solve the problem, given that only 17% of IPD isolates in Indigenous adults in the NT come from the seven serotypes in the currently available vaccine, and 33% would be covered by the 13-valent vaccine under

Acknowledgements

We acknowledge all those involved in the surveillance of IPD in the Northern Territory and those reporting to and maintaining the Adult Immunisation Database, Susan Donath for statistical support, and Kathryn Weston who commented on drafts of this paper.

The National Health and Medical Research Council (ID 384490) & Centre for Clinical Research Excellence (Indigenous Immunisation) provided a Postgraduate Public Health Scholarship for Sarah Moberley.

Conflict of interest statement: No conflicts of

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This chapter summarizes the epidemiology of pneumococcal disease among adults in the United States, available pneumococcal vaccines, and current recommendations regarding their use among adults. Although there has been a decline in vaccine-type invasive pneumococcal disease among adults due to indirect “herd” protection from the use of pneumococcal conjugate vaccines in children, there is still a significant burden. Pneumococcal disease is more common and more severe among adults with underlying conditions that lead to decreased immunity. The Advisory Committee on Immunization Practices currently recommends use of both the 13-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal polysaccharide vaccine in all adults aged >65 years and in adults aged >19 years with certain medical conditions. However, overall pneumococcal vaccine coverage among adults remains low and has not yet met the Healthy People 2020 target.
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We were unable to adjust for the level of chronic illness in our study due to small sample size. Nevertheless, our data supports these findings and may provide some explanation as to the failure in demonstrating a reduction in the high rates of pneumococcal disease experienced throughout life in our study population despite increasing coverage with 23vPPV [1]. Our results suggest that intrinsic genetic differences between Indigenous and non-Indigenous populations may affect immune responsiveness to 23vPPV, although this needs to be explored in more detail.
Indigenous adults residing in the Northern Territory of Australia experience elevated rates of invasive pneumococcal disease despite the routine use of 23-valent pneumococcal polysaccharide vaccine (23vPPV). We hypothesised that the limited protection from 23vPPV may be due to hyporesponsiveness as a result of vaccine failure from repeated vaccination. To explore this possibility, we evaluated the immune response to a first and second dose of 23vPPV in Indigenous adults and a first dose of 23vPPV in non-Indigenous adults.
Serotype-specific IgG was measured by ELISA for all 23 vaccine serotypes at baseline and at one month post-vaccination. Individuals were considered to have an adequate immune response if paired sera demonstrated either: a four-fold rise in antibody concentration; a two-fold rise if the post vaccination antibody was >1.3 μg/ml but <4.0 μg/ml; or a post-vaccination antibody concentration >4.0 μg/ml for at least half of the serotypes tested (12/23). Our per-protocol analysis included the comparison of outcomes for three groups: Indigenous adults receiving a second 23vPPV dose (N = 20) and Indigenous (N = 60) and non-Indigenous adults (N = 25) receiving their first 23vPPV dose.
All non-Indigenous adults receiving a first dose of 23vPPV mounted an adequate immune response (25/25). There was no significant difference in the proportion of individuals with an adequate response using our definition (primary endpoint), with 88% of Indigenous adults mounted an adequate response following first dose 23vPPV (53/60) compared to 70% having an adequate response following a second dose of 23vPPV (14/20; p = 0.05). The risk difference between Indigenous participants receiving first dose compared to non-Indigenous participants receiving first dose was significant when comparing a response threshold of at least 70% (−27%, 95% CI: −43% to −11%; p = 0.01) and 90% (−38%, 95% CI: −60% to −16%; p = 0.006) of serotypes with a positive response.
Indigenous participants demonstrated a poorer response to a first dose 23vPPV compared to their non-Indigenous counterparts, with lower IgG following a second 23vPPV dose. These findings highlight the critical need to evaluate the efficacy of future pneumococcal vaccine programs in the Australian Indigenous populations that recommend repeated doses of 23vPPV.
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A randomized controlled trial in Fiji examined the immunogenicity and effect on nasopharyngeal carriage after 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) in infancy followed by 23-valent pneumococcal polysaccharide vaccine (23vPPV; Pneumovax) at 12 months of age. At 18 months of age, children given 23vPPV exhibited immune hyporesponsiveness to a micro-23vPPV (20%) challenge dose in terms of serotype-specific IgG and opsonophagocytosis, while 23vPPV had no effect on vaccine-type carriage.
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Paired samples were obtained from 185 children. There were no significant differences in the serotype-specific IgG, opsonophagocytosis, or memory B-cell response at either time point between children who did or did not receive 23vPPV at 12 months of age. Nasopharyngeal carriage of PCV7 and 23vPPV serotypes was similar among the groups. Priming with 1, 2, or 3 PCV7 doses during infancy did not affect serotype-specific immunity or carriage.
Immune hyporesponsiveness induced by 23vPPV in toddlers does not appear to be sustained among preschool children in this context and does not affect the pneumococcal carriage rate in this age group.
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The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for all aged ⩾65 years in the UK to help reduce the burden of invasive pneumococcal disease (IPD). A total of 728 IPD cases aged ⩾65 years were diagnosed between 1 April 2006 and 31 July 2012 in the North East of England. Crude vaccine effectiveness (VE) estimates for PPV23 were calculated using the indirect-cohort method using a stratified analysis. VE for persons aged ⩾65 years was 28.5% (95% confidence interval: −17.4%, 56.5%). PPV23 was less effective in older age groups at IPD diagnosis and for those vaccinated at an older age. Estimates of VE published since the introduction of PPV23 appear to show a decrease in VE over time, possibly due to changes in demographics, circulating serotypes and vaccine formulation. An effective PPV23 vaccination programme should continue in those aged ⩾65 years in the North East of England.
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Failure to vaccinate or failure of vaccine? Effectiveness of the 23-valent pneumococcal polysaccharide vaccine program in Indigenous adults in the Northern Territory of Australia

Abstract

Introduction

Section snippets

Enhanced surveillance

Results

Discussion

Conclusions

Acknowledgements

Lancet

Int J Pediatr Otorhinolaryngol

Chest

Eur J Cancer Clin Oncol

Aust NZ J Public Health

Vaccine

Invasive pneumococcal disease in central Australia

Med J Aust

The Health and Welfare of Australia's Aboriginal and Torres Strait Islander Peoples 2005: Australian Bureau of Statistics and Australian Institute of Health and Welfare

What's new in immunisation? Changes to the Australian and Northern Territory Standard Vaccination Schedules

Northern Territory Dis Control Bull

Vaccines for preventing pneumococcal infection in adults

Cochrane Database Syst Rev

Efficacy of pneumococcal vaccination in adults: a meta-analysis

Can Med Assoc J