Estimating seasonal variation in Australian pertussis notifications from 1991 to 2016: evidence of spring to summer peaks.

Unlike for many other respiratory infections, the seasonality of pertussis is not well understood. While evidence of seasonal fluctuations in pertussis incidence has been noted in some countries, there have been conflicting findings including in the context of Australia. We investigated this issue by analysing the seasonality of pertussis notifications in Australia using monthly data from January 1991 to December 2016. Data were made available for all states and territories in Australia except for the Australian Capital Territory and were stratified into age groups. Using a time-series decomposition approach, we formulated a generalised additive model where seasonality is expressed using cosinor terms to estimate the amplitude and peak timing of pertussis notifications in Australia. We also compared these characteristics across different jurisdictions and age groups. We found evidence that pertussis notifications exhibit seasonality, with peaks observed during the spring and summer months (November-January) in Australia and across different states and territories. During peak months, notifications are expected to increase by about 15% compared with the yearly average. Peak notifications for children <5 years occurred 1-2 months later than the general population, which provides support to the theory that older household members remain an important source of pertussis infection for younger children. In addition, our results provide a more comprehensive spatial picture of seasonality in Australia, a feature lacking in previous studies. Finally, our findings suggest that seasonal forcing may be useful to consider in future population transmission models of pertussis.

Pneumonia hospitalisation and case-fatality rates in older Australians with and without risk factors for pneumococcal disease: implications for vaccine policy.

Community-acquired pneumonia (CAP) results in substantial numbers of hospitalisations and deaths in older adults. There are known lifestyle and medical risk factors for pneumococcal disease but the magnitude of the additional risk is not well quantified in Australia. We used a large population-based prospective cohort study of older adults in the state of New South Wales (45 and Up Study) linked to cause-specific hospitalisations, disease notifications and death registrations from 2006 to 2015. We estimated the age-specific incidence of CAP hospitalisation (ICD-10 J12-18), invasive pneumococcal disease (IPD) notification and presumptive non-invasive pneumococcal CAP hospitalisation (J13 + J18.1, excluding IPD), comparing those with at least one risk factor to those with no risk factors. The hospitalised case-fatality rate (CFR) included deaths in a 30-day window after hospitalisation. Among 266 951 participants followed for 1 850 000 person-years there were 8747 first hospitalisations for CAP, 157 IPD notifications and 305 non-invasive pneumococcal CAP hospitalisations. In persons 65-84 years, 54.7% had at least one identified risk factor, increasing to 57.0% in those ⩾85 years. The incidence of CAP hospitalisation in those ⩾65 years with at least one risk factor was twofold higher than in those without risk factors, 1091/100 000 (95% confidence interval (CI) 1060-1122) compared with 522/100 000 (95% CI 501-545) and IPD in equivalent groups was almost threefold higher (18.40/100 000 (95% CI 14.61-22.87) vs. 6.82/100 000 (95% CI 4.56-9.79)). The CFR increased with age but there were limited difference by risk status, except in those aged 45 to 64 years. Adults ⩾65 years with at least one risk factor have much higher rates of CAP and IPD suggesting that additional risk factor-based vaccination strategies may be cost-effective.

Revisiting Styblo's law: could mathematical models aid in estimating incidence from prevalence data?

Estimation of the true incidence of tuberculosis (TB) is challenging. The approach proposed by Styblo in 1985 is known to be inaccurate in the modern era where there is widespread availability of treatment for TB. This study re-examines the relationship of incidence to prevalence and other disease indicators that can be derived from surveys. We adapt a simple, previously published model that describes the epidemiology of TB in the presence of treatment to investigate a revised ratio-based approach to estimating incidence. We show that, following changes to treatment programmes for TB, the ratio of incidence to prevalence reaches an equilibrium value rapidly; long before other model indicators have stabilized. We also show that this ratio relies on few parameters but is strongly dependent on, and requires knowledge of, the efficacy and timeliness of treatment.

Control of varicella in the post-vaccination era in Australia: a model-based assessment of catch-up and infant vaccination strategies for the future.

In Australia, varicella vaccine was universally funded in late 2005 as a single dose at 18 months. A school-based catch-up programme for children aged 10-13 years without a history of infection or vaccination was funded until 2015, when those eligible for universal infant vaccination would have reached the age of high school entry. This study projects the impact of discontinuing catch-up vaccination on varicella and zoster incidence and morbidity using a transmission dynamic model, in comparison with alternative policy options, including two-dose strategies. At current vaccine coverage (83% at 2 years and 90% at 5 years), ceasing the adolescent catch-up programme in 2015 was projected to increase varicella-associated morbidity between 2035 and 2050 by 39%. Although two-dose infant programmes had the lowest estimated varicella morbidity, the incremental benefit from the second dose fell by 70% if first dose coverage increased from 83% to 95% by age 24 months. Overall zoster morbidity was predicted to rise after vaccination, but differences between strategies were small. Our results suggest that feasibility of one-dose coverage approaching 95% is an important consideration in estimating incremental benefit from a second dose of varicella vaccine.

Risk factors for herpes zoster in a large cohort of unvaccinated older adults: a prospective cohort study.

We analysed data from a prospective cohort of 255,024 adults aged ⩾45 years recruited from 2006-2009 to identify characteristics associated with a zoster diagnosis. Diagnoses were identified by linkage to pharmaceutical treatment and hospitalization records specific for zoster and hazard ratios were estimated. Over 940,583 person-years, 7771 participants had a zoster diagnosis; 253 (3·3%) were hospitalized. After adjusting for age and other factors, characteristics associated with zoster diagnoses included: having a recent immunosuppressive condition [adjusted hazard ratio (aHR) 1·58, 95% confidence interval (CI) 1·32-1·88], female sex (aHR 1·36, 95% CI 1·30-1·43), recent cancer diagnosis (aHR 1·35, 95% CI 1·24-1·46), and severe physical limitation vs. none (aHR 1·33, 95% CI 1·23-1·43). The relative risk of hospitalization for zoster was higher for those with an immunosuppressive condition (aHR 3·78, 95% CI 2·18-6·55), those with cancer (aHR 1·78, 95% CI 1·24-2·56) or with severe physical limitations (aHR 2·50, 95% CI 1·56-4·01). The novel finding of an increased risk of zoster diagnoses and hospitalizations in those with physical limitations should prompt evaluation of the use of zoster vaccine in this population.

Influenza-attributable mortality in Australians aged more than 50 years: a comparison of different modelling approaches.

This study aimed to compare systematically approaches to estimating influenza-attributable mortality in older Australians. Using monthly age-specific death data together with viral surveillance counts for influenza and respiratory syncytial virus, we explored two of the most frequently used methods of estimating excess influenza-attributable disease: Poisson and Serfling regression models. These approaches produced consistent age and temporal patterns in estimates of influenza-attributable mortality in older Australians but some variation in the magnitude of the disease burden. Of Australians aged >50 years, average annual estimated influenza-attributable deaths (all cause) ranged from 2314 to 3457 for the Serfling and Poisson regression models, respectively. The excess influenza-attributable disease burden was substantial under all approaches.

Delay-adjusted age- and sex-specific case fatality rates for COVID-19 in South Korea: Evolution in the estimated risk of mortality throughout the epidemic.

OBJECTIVES: The aim of this study was to estimate delay-adjusted case fatality rates (CFRs) for COVID-19 in South Korea, and evaluate how these estimates have evolved over time throughout the epidemic. METHODS: Public data from the Korea Centers for Disease Control and Prevention (KCDC) were used to estimate age- and sex-specific CFRs for COVID-19 in South Korea up to June 12, 2020. We applied statistical methods previously developed to adjust for the delay between diagnosis and death, and presented both delay-adjusted and crude (unadjusted) CFRs throughout the epidemic. RESULTS: The overall estimated delay-adjusted CFR was 2.39% (3.05% for males and 1.92% for females). Within each age strata where deaths were reported, males were found to have significantly higher CFRs than females. The estimated CFRs increased substantially from age 60 years in males and from 70 years in females. Both the delay-adjusted and crude CFRs were found to have evolved substantially, particularly early in the epidemic, converging only from mid-April 2020. CONCLUSIONS: The CFRs for South Korea provide an estimate of mortality risk in a setting where case ascertainment is likely to be more complete. The evolution in CFRs throughout the epidemic highlights the need for caution when interpreting CFRs calculated at a given time point.

Evolution over time in the cost-effectiveness of pneumococcal conjugate vaccine (PCV13) in older Australians due to herd protection from infant vaccination.

In many settings, serotype changes as a result of infant 13-valent pneumococcal conjugate vaccine (PCV13) programs are likely to continue after the introduction of adult PCV13 programs. We applied a multi-cohort model to explore how potential serotype changes may impact on the cost-effectiveness of PCV13 use in Australian adults aged over 65 years. We found assumptions around continued herd protection from infant PCV13 programs to be critical when assessing the cost-effectiveness of adult PCV13 vaccination in Australia. Future cost-effectiveness analyses of adult PCV13 programs need to carefully consider how to predict these future changes in serotypes, with Australian data suggesting that the changes post-PCV13 use in infants may be different than post-PCV7.

Within-season influenza vaccine waning suggests potential net benefits to delayed vaccination in older adults in the United States.

BACKGROUND: There is growing evidence that there is within (intra-) season waning of influenza vaccine protection in older adults, suggesting there may be a benefit to giving influenza vaccine closer to the time of increased infection risk. We aimed to quantitatively evaluate the impact of modifying the timing of influenza vaccination in U.S. older adults. METHODS: Using historical data (2010/2011-2015/2016, inclusive) on influenza activity and vaccine uptake, we explore the optimal time to begin vaccinating older adults (≥65 years) in the U.S. to maximize prevention of influenza. We modelled the effect of changing the timing of vaccination by estimating the percentage change to the current disease burden and used this to calculate the estimated optimal week to begin vaccination in the U.S. RESULTS: When we assumed a relatively slower waning protection rate (over 52 weeks), the estimated optimal time to begin vaccinating those aged ≥65 years varied between mid-August (week 34, 2012-2013) and mid-late October (week 43, 2011-2012) depending on the season, resulting in 0.44% and 5.11% of the current disease burden prevented respectively. Under faster waning (over 26 weeks), the estimated optimal week varied between early September (week 37, 2012-2013) and mid-November (week 47, 2011-2012), resulting in 3.69% and 11.97% of the current disease burden prevented respectively. CONCLUSIONS: While it is difficult to determine the ideal time to start to vaccinate due to substantial variation in timing of individual seasons, we found that there are potentially substantial benefits to minimizing the time between vaccination and influenza activity in U.S. older adults. Modest delays in immunization were beneficial in the seasons we evaluated. If further evidence suggests fast waning, longer delays may be warrant as in these scenarios the timing of the current vaccination was often very suboptimal.

Retrospective cost-effectiveness of the 23-valent pneumococcal polysaccharide vaccination program in Australia.

BACKGROUND: The Australian infant pneumococcal vaccination program was funded in 2005 using the 7-valent pneumococcal conjugate vaccine (PCV7) and the 13-valent conjugate vaccine (PCV13) in 2011. The PCV7 and PCV13 programs resulted in herd immunity effects across all age-groups, including older adults. Coincident with the introduction of the PCV7 program in 2005, 23-valent pneumococcal polysaccharide vaccine (PPV23) was funded for all Australian adults aged over 65 years. METHODS: A multi-cohort Markov model with a cycle length of one year was developed to retrospectively evaluate the cost-effectiveness of the PPV23 immunisation program from 2005 to 2015. The analysis was performed from the healthcare system perspective with costs and quality-adjusted life years discounted at 5% annually. The incremental cost-effectiveness ratio (ICER) for PPV23 doses provided from 2005 to 2015 was calculated separately for each year when compared to no vaccination. Parameter uncertainty was explored using deterministic and probabilistic sensitivity analysis. RESULTS: It was estimated that PPV23 doses given out over the 11-year period from 2005 to 2015 prevented 771 hospitalisations and 99 deaths from invasive pneumococcal disease (IPD). However, the estimated IPD cases and deaths prevented by PPV23 declined by more than 50% over this period (e.g. from 12.9 deaths for doses given out in 2005 to 6.1 in 2015), likely driven by herd effects from infant PCV programs. The estimated ICER over the period 2005 to 2015 was approximately A$224,000/QALY gained compared to no vaccination. When examined per year, the ICER for each individual year worsened from $140,000/QALY in 2005 to $238,000/QALY in 2011 to $286,000/QALY in 2015. CONCLUSION: The cost-effectiveness of the PPV23 program in older Australians was estimated to have worsened over time. It is unlikely to have been cost-effective, unless PPV23 provided protection against non-invasive pneumococcal pneumonia and/or a low vaccine price was negotiated. A key policy priority should be to review of the future use of PPV23 in Australia, which is likely to be more cost-effective in certain high-risk groups.

Pertussis vaccination in a cohort of older Australian adults following a cocooning vaccination program.

BACKGROUND: While recommendations to vaccinate adults against pertussis exist, information on uptake for adult tetanus-diphtheria-pertussis vaccine (Tdap) among older adults is limited. METHODS: We used data from the 45 and Up Study, a prospective cohort of adults aged ≥45 years who completed a questionnaire between 2012 and 2014 asking about pertussis vaccination. We evaluated Tdap uptake following a program providing free vaccine for adults in contact with young children between 2009 and 2012. RESULTS: Among 91,432 adults (mean age = 66.3 years, SD = 9.6), 3.1% (n = 2823) reported receiving Tdap prior to the program. This increased seven-fold to 21.8% (n = 19898) after the program finished. Tdap coverage was almost twice as high in women compared to men and among adults more likely to be grandparents than those not. CONCLUSION: These findings suggest that funding for a targeted program can help to substantially increase vaccination coverage as well as decrease disparities in the uptake of Tdap in different sub-groups.

The role of timeliness in the cost-effectiveness of older adult vaccination: A case study of pneumococcal conjugate vaccine in Australia.

While the impact of the timeliness of vaccine administration has been well-studied for childhood vaccinations, there has been little detailed quantitative analysis on the potential impact of the timeliness of vaccinations in older adults. The aim of this study was to explore the impact of implementing more realistic observed uptake distributions, taking into the account reduced vaccine efficacy but higher pneumococcal disease burden with increasing age beyond 65 years. A multi-cohort Markov model was constructed to evaluate the cost-effectiveness of a pneumococcal (PCV13) immunisation program in Australia, assuming two different uptake modelling approaches. The approach using an estimate of observed uptake was compared with a scenario in which the total cumulative uptake was delivered at the recommended age of vaccination. We found these two approaches produced different results both in terms of cases prevented and cost-effectiveness. The impact of the non-timely uptake in adult programs may sometimes have positive and other times negative effects, depending on several factors including the age-specific disease rates and the duration of vaccine protection. Our study highlights the importance of using realistic assumptions around uptake (including non-timely vaccination) when estimating the impact of vaccination in adults.

Cost-effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) in older Australians.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPV23) has been funded under the Australia National Immunisation Program (NIP) since January 2005 for those aged >65years and other risk groups. In 2016, PCV13 was accepted by the Pharmaceutical Benefits Advisory Committee (PBAC) as a replacement for a single dose of PPV23 in older Australian adults. METHODS: A single-cohort deterministic multi-compartment (Markov) model was developed describing the transition of the population between different invasive and non-invasive pneumococcal disease related health states. We applied a healthcare system perspective with costs (Australian dollars, A$) and health effects (measured in quality adjusted life-years, QALYs) attached to model states and discounted at 5% annually. We explored replacement of PPV23 with PCV13 at 65years as well as other age based vaccination strategies. Parameter uncertainty was explored using deterministic and probabilistic sensitivity analysis. RESULTS: In a single cohort, we estimated PCV13 vaccination at the age of 65years to cost ∼A$11,120,000 and prevent 39 hospitalisations and 6 deaths from invasive pneumococcal disease and 180 hospitalisations and 10 deaths from community acquired pneumonia. The PCV13 program had an incremental cost-effectiveness ratio of ∼A$88,100 per QALY gained when compared to a no-vaccination, whereas PPV23 was ∼A$297,200 per QALY gained. To fall under a cost-effectiveness threshold of A$60,000 per QALY, PCV13 would have to be priced below ∼A$46 per dose. The cost-effectiveness of PCV13 in comparison to PPV23 was ∼A$35,300 per QALY gained. CONCLUSION: In comparison to no-vaccination, we found PCV13 use in those aged 65years was unlikely to be cost-effective unless the vaccine price was below A$46 or a longer duration of protection can be established. However, we found that in comparison to the PPV23, vaccination with PCV13 was cost-effective. This partly reflects the poor value for money estimated for PPV23 use in Australia.

Beyond expectations: Post-implementation data shows rotavirus vaccination is likely cost-saving in Australia.

BACKGROUND: Universal vaccination against rotavirus was included in the funded Australian National Immunisation Program in July 2007. Predictive cost-effectiveness models assessed the program before introduction. METHODS: We conducted a retrospective economic evaluation of the Australian rotavirus program using national level post-implementation data on vaccine uptake, before-after measures of program impact and published estimates of excess intussusception cases. These data were used as inputs into a multi-cohort compartmental model which assigned cost and quality of life estimates to relevant health states, adopting a healthcare payer perspective. The primary outcome was discounted cost per quality adjusted life year gained, including or excluding unspecified acute gastroenteritis (AGE) hospitalisations. RESULTS: Relative to the baseline period (1997-2006), over the 6years (2007-2012) after implementation of the rotavirus program, we estimated that ∼77,000 hospitalisations (17,000 coded rotavirus and 60,000 unspecified AGE) and ∼3 deaths were prevented, compared with an estimated excess of 78 cases of intussusception. Approximately 90% of hospitalisations prevented were in children <5years, with evidence of herd protection in older age groups. The program was cost-saving when observed changes (declines) in both hospitalisations coded as rotavirus and as unspecified AGE were attributed to the rotavirus vaccine program. The adverse impact of estimated excess cases of intussusception was far outweighed by the benefits of the program. CONCLUSION: The inclusion of herd impact and declines in unspecified AGE hospitalisations resulted in the value for money achieved by the Australian rotavirus immunisation program being substantially greater than predicted bypre-implementation models, despite the potential increased cases of intussusception. This Australian experience is likely to be relevant to high-income countries yet to implement rotavirus vaccination programs.

What do we know about the cost-effectiveness of pneumococcal conjugate vaccination in older adults?

The cost-effectiveness of 13-type pneumococcal conjugate vaccine (PCV13) use in older adults, and the relative merits when compared to the 23-type polysaccharide pneumococcal vaccine (PPV23), has been a topic of much debate. Although a number of economics evaluations have been conducted many of these were completed before the availability of critical data on PCV13 efficacy in older adults. Recent studies using this data have found conflicting results. This may in part reflect differences in the level of herd protection from infant pneumococcal vaccination programs in different countries. The costs and benefits of pneumococcal vaccination in adults are likely to rest on several critical parameters: the magnitude pneumococcal disease in older adults and the serotypes responsible for it, the efficacy of each vaccine against invasive and non-invasive pneumonia, the duration of vaccine protection, and differences in vaccine price. The ongoing changes in pneumococcal disease patterns highlight the need for economic evaluations to use recent serotype-specific disease estimates from the setting under consideration. In countries that do recommend PCV13 use in adults, post-implementation economic evaluation (using data from after a program is implemented) may be useful to help inform potential future changes to vaccine recommendations as well as the maximum price that should be paid for the vaccines in future negotiations.

Retrospective economic evaluation of childhood 7-valent pneumococcal conjugate vaccination in Australia: Uncertain herd impact on pneumonia critical.

BACKGROUND: Retrospective cost-effectiveness analyses of vaccination programs using routinely collected post-implementation data are sparse by comparison with pre-program analyses. We performed a retrospective economic evaluation of the childhood 7-valent pneumococcal conjugate vaccine (PCV7) program in Australia. METHODS: We developed a deterministic multi-compartment model that describes health states related to invasive and non-invasive pneumococcal disease. Costs (Australian dollars, A$) and health effects (quality-adjusted life years, QALYs) were attached to model states. The perspective for costs was that of the healthcare system and government. Where possible, we used observed changes in the disease rates from national surveillance and healthcare databases to estimate the impact of the PCV7 program (2005-2010). We stratified our cost-effectiveness results into alternative scenarios which differed by the outcome states included. Parameter uncertainty was explored using probabilistic sensitivity analysis. RESULTS: The PCV7 program was estimated to have prevented ∼5900 hospitalisations and ∼160 deaths from invasive pneumococcal disease (IPD). Approximately half of these were prevented in adults via herd protection. The incremental cost-effectiveness ratio was ∼A$161,000 per QALY gained when including only IPD-related outcomes. The cost-effectiveness of PCV7 remained in the range A$88,000-$122,000 when changes in various non-invasive disease states were included. The inclusion of observed changes in adult non-invasive pneumonia deaths substantially improved cost-effectiveness (∼A$9000 per QALY gained). CONCLUSION: Using the initial vaccine price negotiated for Australia, the PCV7 program was unlikely to have been cost-effective (at conventional thresholds) unless observed reductions in non-invasive pneumonia deaths in the elderly are attributed to it. Further analyses are required to explore this finding, which has significant implications for the incremental benefit achievable by adult PCV programs.

A review of economic evaluations of 13-valent pneumococcal conjugate vaccine (PCV13) in adults and the elderly.

The 13-valent pneumococcal conjugated vaccine (PCV13) is already recommended for some adult groups and is being considered for wider use in many countries. In order to identify the strengths and limitations of the existing economic evaluation studies of PCV13 in adults and the elderly a literature review was conducted. The majority of the studies identified (9 out of 10) found that PCV13 was cost-effective in adults and/or the elderly. However, these results were based on assumptions that could not always be informed by robust evidence. Key uncertainties included the efficacy of PCV13 against non-invasive pneumonia and the herd immunity effect of childhood vaccination programs. Emerging trial evidence on PCV13 in adults from the Netherlands offers the ability to parameterize future economic evaluations with empirical efficacy data. However, it is important that these estimates are used thoughtfully when they are transferred to other settings.

Are current cost-effectiveness thresholds for low- and middle-income countries useful? Examples from the world of vaccines.

The World Health Organization's CHOosing Interventions that are Cost Effective (WHO-CHOICE) thresholds for averting a disability-adjusted life-year of one to three times per capita income have been widely cited and used as a measure of cost effectiveness in evaluations of vaccination for low- and middle-income countries (LMICs). These thresholds were based upon criteria set out by the WHO Commission on Macroeconomics and Health, which reflected the potential economic returns of interventions. The CHOICE project sought to evaluate a variety of health interventions at a subregional level and classify them into broad categories to help assist decision makers, but the utility of the thresholds for within-country decision making for individual interventions (given budgetary constraints) has not been adequately explored. To examine whether the 'WHO-CHOICE thresholds' reflect funding decisions, we examined the results of two recent reviews of cost-effectiveness analyses of human papillomavirus and rotavirus vaccination in LMICs, and we assessed whether the results of these studies were reflected in funding decisions for these vaccination programmes. We found that in many cases, programmes that were deemed cost effective were not subsequently implemented in the country. We consider the implications of this finding, the advantages and disadvantages of alternative methods to estimate thresholds, and how cost perspectives and the funders of healthcare may impact on these choices.