|dc.description.abstract||Passive immunisation is an important means of preventing communicable diseases post-exposure, particularly for subpopulations most vulnerable to complications from infection. The blood product normal human immunoglobulin (NHIG) is used in Australia for post-exposure prophylaxis in certain non-immune populations to prevent measles and hepatitis A and is recommended in certain circumstances for non-immune pregnant women to prevent rubella and congenital rubella syndrome. Practices with respect to passive immunisation post-exposure for these conditions vary around the globe and importantly, vary among countries similar to Australia such as New Zealand, the United Kingdom and the United States. The series of studies presented here aimed to understand the possible reasons behind these differences in practice and, using this information, make recommendations for the most effective and efficient use of NHIG in public health practice in Australia.
An overview of passive immunisation, rubella, measles, and hepatitis A and the public health management of these conditions, current at the time of thesis commencement, is provided. This is followed by an exploration of why practices of passive immunisation post-exposure to measles, rubella and hepatitis A might vary among high-income countries, concluding that a lack of collated evidence of the effectiveness of passive immunisation for preventing measles and rubella, unanswered questions about the minimum effective doses of NHIG as post-exposure prophylaxis for each disease, and differences in disease-specific antibodies in available immunoglobulin products may be significant.
To redress these deficits, two systematic reviews collated existing evidence of the effectiveness of passive immunisation for preventing measles, and rubella and congenital rubella syndrome; disease-specific antibody concentrations were measured in samples of Australian blood products used for passive immunisation; and simulation modelling validated by the preliminary results of a clinical trial were used to estimate the minimum effective doses of NHIG required for post-exposure prophylaxis for each disease. A budgetary impact assessment was then conducted utilising the data from a study of NHIG usage in Australia to examine the financial implications of the recommended changes to passive immunisation practice in Australia made as a result of the newly available evidence.
The first systematic review collated and synthesised the evidence of the effectiveness of passive immunisation for preventing measles post-exposure concluding that passive immunisation is effective for preventing measles up to seven days post-exposure and that a dose-response is likely. The second systematic review collated and synthesised the evidence of the effectiveness of passive immunisation for preventing rubella and congenital rubella syndrome post-exposure concluding that passive immunisation seems to be effective for preventing rubella up to five days post-exposure, but that insufficient evidence exists to directly examine effectiveness for preventing congenital rubella syndrome. Again, a dose-response seemed likely.
The concentrations of measles and rubella antibodies in Australian NHIG and intravenous immunoglobulin (IVIG) were quantified. Measles titres in Australian NHIG ranged from 51 to 76 IU/mL and those in IVIG ranged from 6 to 24 IU/mL as measured by the plaque-reduction neutralisation test. The minimum concentration of rubella antibodies measured in Australian NHIG was 2108 IU/mL, while in Australian IVIG it was 268 IU/mL as measured by a chemiluminescent assay. Australian NHIG is made to the European Pharmacopoeia standard of 100 IU/mL of hepatitis A antibodies, so these were not further quantified.
Pharmacokinetic modelling using a two-compartment model with first order absorption estimated the minimum effective doses of NHIG required to prevent measles, rubella and hepatitis A. The minimum effective dose of measles-specific antibodies was estimated as 25.5 IU/kg. The minimum effective dose of rubella-specific antibodies was estimated as less than 13 IU/kg. The minimum effective dose of hepatitis Aspecific antibodies was estimated at 3.6 IU/kg. Model predictions of serum concentrations of hepatitis A antibodies seemed consistent with the preliminary results of the clinical trial of NHIG administration to healthy non-immune volunteers.
Comparing the estimated minimum effective doses alongside the evidence of effectiveness with current practice resulted in the following recommendations for alterations to post-exposure passive immunisation in Australia:
* For measles control: Increase the dose of NHIG recommended to 0.5 mL/kg without a volume limit. Where calculated doses are large, consider including the option of intravenous IG dosing and if this is adopted, limit the recommendations for post-exposure passive immunisation to those most vulnerable to measles complications.
* For rubella control: Decrease the dose of NHIG to 0.5 mL for non-immune pregnant women weighing up to 160kg or 1 mL for those weighing greater than 160 kg. Offer post-exposure passive immunisation within five days of first exposure followed by serial serology to enable identification of asymptomatic disease.
* For hepatitis A control: Individual clinical assessment may indicate an increased dose is warranted for contacts weighing more than 85 kg. In this case, the recommended dose is 0.036 mL/kg.
The use of NHIG in public health practice in Queensland and Australia over a decade was documented from routinely collected data, highlighting that NHIG was used variably for measles post-exposure prophylaxis, rarely for hepatitis A post-exposure prophylaxis and hadn’t been documented for rubella post-exposure prophylaxis. The potential budgetary impact at a national level of implementing the recommended changes to passive immunisation practice using the cost calculator method was found to be minimal, even in a ‘worst case’ scenario analysis where the maximal spend was for measles control and was less than AU$350 000 per year. When the scenario for analysis approximated historical estimates, implementing the recommended changes was either approximately equal in cost to current practice, or cost saving.
It was therefore concluded that public health practice with respect to passive immunisation post-exposure to measles, rubella and hepatitis A should change in Australia in line with the above recommendations.
Adoption of the recommendations of this program of research on the effectiveness and efficiency of passive immunisation for the public health management of measles, rubella and hepatitis A in Australia may improve the effectiveness of this intervention and either minimally impact on government health spending or be cost saving. A number of the studies contained herein provide valid benchmarks for future research or quality audits, including the first published concentrations of measles and rubella antibodies in Australian NHIG and IVIG, and the first published Australian usage of NHIG for post-exposure prophylaxis. At a global level, the systematic reviews of effectiveness of passive immunisation for preventing measles and rubella and congenital rubella post-exposure, and also the published pharmacokinetic model, have application for countries revising their own public health guidelines.||