Journal Club summaries - 2011

Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial

Griffiths PD, Stanton A, McCarrell E, et al.
The Lancet 377(9773):1256-63.
Link to abstract

Cytomegalovirus (CMV) infection remains a significant pathogen in pregnant women, immunosuppressed patients, in particular those with AIDS, and people who have received either haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT). CMV can remain latent and therefore reinfect despite pre-existing immunity. Disseminated CMV infection in transplant patients can result in end stage organ failure. Currently there are two modes of treatment. Pre-emptive treatment involves monitoring for CMV infection and commencing treatment once CMV viraemia reaches a predefined threshold, or antiviral prophylaxis pre-transplant.

The source of the CMV infection is the challenge to the development of an effective CMV vaccine. Infection can arise from the donor organ or from reactivation in the recipient. The infection can be due to a seronegative or previously immune recipient being infected with a new strain of CMV. The recipient who acquires donor-derived CMV is at greatest risk of end stage disease.

The authors undertook a phase II randomised, placebo-controlled trial in adults who were waiting for either a kidney or liver transplant. The vaccine consisted of 20 µg of a recombinant CMV glycoprotein B adjuvanted with MF59. This vaccine was administered intramuscularly at 0, 1 and 6 months. Where a patient received a transplant while enrolled in the trial, no further vaccines were administered. Patients in the placebo arm of the trial received normal saline. Outcomes were adverse events monitoring and immunogenicity.

The most commonly reported side effect was injection site pain.
Glycoprotein B antibodies were significantly increased 1 month post dose 2 in comparison to placebo for both patients who were initially seronegative or immune to CMV. For those patients who proceeded to transplantation and who subsequently were observed to have a CMV viraemia, the duration of CMV viraemia was significantly reduced which also reduced the number of days on pre-emptive therapy (ganciclovir or valganciclovir).

This study shows great promise, in particular for vaccination of CMV naïve recipients, and also demonstrated the potential for the use of this vaccine as a booster to circumvent reactivation. This vaccine may also be beneficial to women of childbearing age. Further trials are planned with this candidate vaccine.

Presented by Dr Jane Jelfs, Manager, Policy Support, NCIRS

Overview of the New Zealand National Immunisation Conference, Rotorua, August 2011

Kirsten Ward, Evaluation Project Officer, NCIRS, and Kath Cannings, Immunisation CNC, NCIRS, gave a summary of a selection of presentations from the New Zealand Immunisation Conference held in Rotorua in August 2011. A key theme that featured in many of the presentations was the importance of building trust between the immunisation provider and the patient. The achievement of 90% coverage of children aged 2 years was celebrated, with the new goal for 95% and strategies to achieve this presented. Individual conference presentations are available online at http://imac2011.co.nz/

Presented by Kirsten Ward, Evaluation Project Officer, and Kath Cannings, Immunisation CNC, NCIRS

Causality assessment of serious neurologic adverse events following 2009 H1N1 vaccination

Williams SE, Pahud BA, Vellozzi C, et al.
Vaccine 2011 Sep 2. [Epub ahead of print]
Link to abstract

Following widespread use of the H1N1 vaccine in the United States during the fall of 2009, this study aimed to assess the possible causal relationship of the H1N1 vaccine to Guillain-Barré Syndrome (GBS) because of the reported increase in GBS case reports following immunisation with the 1976 swine flu vaccine.

The current causality criteria to assess causality between an adverse event following immunisation (AEFI) and administered vaccine were developed by the World Health Organization (WHO) and have been used globally (JP Collet, N MacDonald, N Cashman and R Pless. Monitoring signals for vaccine safety: the assessment of individual adverse event reports by an expert advisory committee. Advisory Committee on Causality Assessment. Bull World Health Organ 2000;78(2):178-85.) However, the WHO causality criteria are based primarily on the temporal relationship between vaccination and onset of the adverse event, and have thus been questioned for not adequately accounting for other more likely potential causes of the adverse event or considering the evidence supporting such an association. For example, the WHO causality assessment of “possible” stipulates that the AEFI “could also be explained by a concurrent disease or other drugs or chemicals”. Thus, a patient with both a concurrent infection and an antecedent vaccination could meet the “possible” criteria even though the concurrent infection represented a more likely cause.

To overcome these apparent limitations of WHO causality criteria, the criteria were modified and named as CISA-modified WHO criteria for purposes of causality assessment in this study (CISA = Clinical Immunization Safety Assessment network). According to the CISA-modified WHO criteria the other more likely possible causes should be excluded before a case can be classified as possibly related to vaccination. The revised criteria also explicitly incorporated the strength of the existing evidence for a causal relationship between the vaccine and adverse event of interest.

Although the modified version of the WHO criteria more thoroughly addressed components of causality assessment for individual reports of AEFI, work is in progress towards a more detailed algorithmic approach for assessing causality in individual cases to illustrate the complexity of the multiple steps and factors that are necessary to consider when assessing causality.

The authors proposed that causal assessment of serious AEFI reported through the Vaccine Adverse Event Reporting System (VAERS), although challenging, could be enhanced by development and introduction of structured protocols for the evaluation of specific AEFI to rule out other causes of the event. Providers would need to be educated on the importance of referring to these protocols if there is concern that an AEFI may be causally related to the administered vaccine. Improved communication with reporting providers at the time of the AEFI workup would greatly enhance the quality of information necessary for a more fully informed causal assessment utilising thorough case histories, laboratory evaluation, imaging and electrophysiological testing. This approach could maximise the ability to address causality through VAERS reports more quickly and accurately in an effort to add to our overall knowledge of vaccine safety.

Presented by Dr Deepika Mahajan, Senior Research Officer, NCIRS

Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study

Miller E, Andrews NJ, Waight PA, et al.
Lancet Infectious Diseases 2011 May 26. [Epub ahead of print]
Link to abstract

Miller and colleagues present findings of their analysis of invasive pneumococcal disease (IPD) data from the United Kingdom’s notifiable disease surveillance system. In order to investigate the impact of 7-valent pneumococcal conjugate vaccination (PCV7) on the epidemiology of IPD, notification data collected prior to the introduction of PCV7, between 2000 and 2006, was compared to notification data collected in 2009 and 2010 following introduction of PCV7. Serotype-specific analyses were undertaken to investigate natural tends in IPD epidemiology and identify emergent serotypes.

Between the pre- and post-vaccine periods, an overall 34% reduction in IPD was observed. The most significant decreases were seen in children, particularly those under 2 years of age (98%). A reduction in IPD was also observed in adults aged over 65 years (19%), suggesting an indirect benefit of PCV7 in older age groups. However, these reductions were offset by increases in non-vaccine serotype IPD, particularly serotypes 7F, 19A and 22F. There was no apparent increase in antimicrobial resistance of non-vaccine serotypes following the introduction of PCV7.

In conclusion the authors summarise that PCV7 has achieved a substantial reduction in IPD, despite serotype replacement. This study highlights the importance of robust surveillance systems for IPD, especially in the current context of the introduction of higher valency vaccines.

Presented by Chris Lowbridge, Public Health Officer Trainee, NCIRS

Randomised cluster trial to support informed parental decision-making for the MMR vaccine

Jackson C, Cheater F, Harrison W, et al.
BMC Public Health 2011;11:475.
Link to abstract

In response to public concern about the safety of MMR vaccine in the UK, an educational intervention in the form of a facilitated parent meeting was developed in order to reduce decisional conflict experienced by parents making a vaccination decision for their children.

The intervention was assessed by a randomised cluster trial conducted in Leeds, England. Parents were recruited from childcare and healthcare facility registers, and randomised by cluster into the intervention group who received an information leaflet and attended the facilitated information meeting, and the control group, who received only the leaflet. The primary outcome measure was decisional conflict suffered by parents (measured using the Decisional Conflict Scale), with secondary outcomes including self-reported measures of intended and actual uptake of the vaccine, attitudes and beliefs surrounding MMR vaccine, and knowledge and anxiety. Outcomes were measured by survey prior to randomisation, and at 1 week and 3 months post intervention.

Decisional conflict decreased in both the intervention and control arms of the study, with no statistically significant difference demonstrated between the two. Heightened decisional conflict was reported by parents who were making the vaccination decision for their first child, those who were concerned, and those who had felt less positive toward the vaccine. A statistically significant difference was reported in the actual uptake of the vaccine among intervention parents, when compared with the control parents; however this level of significance was relatively modest (93% versus 73%, p=0.04).

This study had a relatively small sample size, which may have impacted the ability to detect a statistically significant difference between groups. The authors report their surprise at finding both the control and intervention had a positive effect on decisional conflict. The leaflet was used as the control, as it was seen as standard practice. However, many parents reported that this was not in fact the case, indicating that simply engaging parents who are facing an MMR decision for their child might be helpful in reducing their decisional conflict.

Presented by Kerrie Wiley, Research Assistant, NCIRS

Mumps complications and effects of mumps vaccination, England and Wales, 2002-2006

Yung CF, Andrews N, Bukasa A, et al.
Emerging Infectious Diseases 2011;17(4):661-7.
Link to abstract

Presented by Dr Andrew Habig, Public Health Registrar, NCIRS

Vaccine interference:

Comparative effects of carrier proteins on vaccine-induced immune response

Knuf M, Kowalzik F, Kieninger D.
Vaccine 2011;29(31):4881-90.
Link to abstract

The efficacy of vaccines against major encapsulated bacterial pathogens – Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b (Hib) – has been significantly enhanced by conjugating the respective polysaccharides with different carrier proteins. Five carrier proteins are in use at present: diphtheria toxoid; non-toxic cross-reactive material of diphtheria toxin (CRM197); tetanus toxoid (TT); N. meningitidis outer membrane protein (OMP); and non-typeable H. influenzae-derived protein D. There is no absolute safety benefit of one carrier protein over another; however, OMP and TT have slightly higher injection site reaction rates. Data are conflicting as to which carrier protein is the most immunogenic. Coadministration of conjugate vaccines bearing the same carrier protein has the potential for inducing either positive or negative effects on vaccine immunogenicity (immune interference). Clinical studies on the co-administration of conjugate vaccines reveal conflicting data with respect to immune interference and it is not definitively known how this impacts on vaccine efficacy, except for UK reports of reduced immunogenicity to meningocococcal vaccine.

and

Glycoconjugate vaccines and immune interference: a review

Dagan R, Poolman J, Siegrist CA.
Vaccine 2010;28(34):5513-23.
Link to abstract

Bacterial polysaccharide-protein conjugate vaccines (Haemophilus influenzae type b [Hib], pneumococcal and meningococcal conjugates) have revolutionised paediatric vaccination strategies. However, vaccine interference between carrier protein and polysaccharide can impact positively or negatively on immunogenicity. There are three main mechanisms of vaccine interference:
- carrier-specific enhancement of T cell help
- carrier-induced epitopic suppression
- bystander interference.
Multivalent conjugates using TT seem to be at risk for reduced polysaccharide responses. Multivalent CRM197 conjugates are at lower risk for this, but may be at higher risk of inducing bystander interference, particularly affecting Hib and hepatitis B immune responses. As infants receive many vaccines administered either simultaneously or sequentially, investigation for potential vaccine interference is needed, particularly when a new vaccine combination is introduced. However, predicting the interference is problematic as is interpretation of any impact on vaccine effectiveness.

Presented by Dr Nick Wood, Senior Clinical Research Fellow, NCIRS

Susceptibility to vaccine preventable diseases among NSW prison entrants

Guest speaker: Dr Sarah Larney
Senior Research Officer, Centre for Health Research in Criminal Justice, Justice Health, Pagewood

Dr Sarah Larney from Justice Health presented insights and data obtained from a questionnaire and serosurvey undertaken among new inmates within the NSW Justice system.

Sarah laid the foundation regarding the health state of NSW inmates with alarming statistics regarding the complexity of issues facing inmates and Justice Health staff caring for this population. The vast majority of inmates are from the most marginalised and disadvantaged parts of our society. Many spend less than 6 months in prison; however, more than 65% have already had previous prison time. Males (93%) outnumber females (7%) in the prison system but the number of females is increasing. The younger age groups are over-represented in the prison system with approximately 55% aged <35 years. Our Indigenous population is also over-represented with 22% of inmates identifying as Indigenous.

The 2010 NSW Health Inmate Survey reported that placement as a child, unemployment, having a parent in prison and being homeless were associated with a large proportion of inmates. More than 80% reported a mental illness and 53% of males reported a prior head injury that resulted in unconsciousness. With regards to drug abuse, among male inmates, smoking and alcohol abuse were the most commonly reported drug, whereas women inmates reported opioid abuse most commonly.

Justice Health falls under the umbrella of NSW Health and is independent of NSW Prison Services. There are multiple arms of Justice Health including primary care, population health, women’s health, Indigenous health, drug and alcohol, mental health, adolescent health and forensic health.

Transmission of disease within the prison population and visiting populace is readily possible. There are dozens of entries each day through prison receptions, visitor day or work release, court attendances, shared cells, shared showers, recreation areas and other visitor contact.

Approximately 3% of the prison population are HBsAg positive but hepatitis C is the most common blood borne disease. Either hepatitis B or C is acquired through shared IV drug apparatus through ‘home-made’ syringes/needles and in-prison tattooing devices. Sex, while a mode of transmission, is not as common as the wider public thinks.

Justice Health has implemented a vaccination policy. At reception inmates are offered hepatitis B vaccination where there is no prior history. In 2009/2010, 3,603 inmates were vaccinated. Hepatitis A is offered on a risk assessment basis in terms of OHS, whether they are HIV or HepB/C positive or if the inmate suffers from liver cirrhosis or liver failure.

Influenza (annually) and pneumococcal vaccination are also offered to inmates based on risk factors. Other vaccines such as MMR are used in outbreak situations, as was the case in 2010. Immunosuppressed inmates are assessed and offered vaccination as required. The reasons underlying the prevalence of VPDs within prisons was thought to be potentially due to missed childhood vaccinations and increased exposures.

There are seven prison receptions in NSW and, during 2010, 311 new inmates (not prison-to-prison transfers) were asked to participate in a questionnaire and serosurvey. 211 agreed but unfortunately women were under-represented in this sample. ICPMR undertook the serology for HBsAb, MMR and varicella. Community data was also weighted to match sex and age of the inmates for comparison. Of the 211 inmate participants more than a third reported being homeless and 71% did not complete schooling to year 10 level. Serosurvey results indicated that 13% were susceptible to measles, 41% were susceptible to mumps, 16% susceptible to rubella and 10% susceptible to varicella. 52% were found to be HBsAb negative and, of these, more were susceptible among those who have never been in prison previously and who had no IV drug use. Of the 45% found to be immune, 26% reported prior hepatitis B infection and 64% reported prior hepatitis B vaccination. The final 3% were found to be chronic hepatitis B carriers. There appeared to be decreased susceptibility to these VPDs in comparison with the community-matched sera.

Further steps include attempting to increase the prison population willing to partake in these surveys and to engage clinical staff to increase participation. It is also important to increase the female inmate participation rate.

Effectiveness of seasonal influenza vaccine against pandemic (H1N1) 2009 virus, Australia, 2010

Fielding JE, Grant KA, Garcia K, Kelly HA.
Emerging Infectious Diseases 2011;17(7):1181-7.
Link to abstract

Fielding et al. conducted a test-negative case-control study to estimate vaccine effectiveness (VE) of 2010 southern hemisphere trivalent influenza vaccine (TIV) and monovalent pandemic H1N1 (pH1N1) vaccine in Victoria, Australia, through a sentinel surveillance network (involving 87 GPs) for influenza-like illness (ILI). Cases were defined as ILI + pH1N1 positive and controls were those with ILI + negative to any influenza virus. They showed that pH1N1 was the dominant strain in 2010. There were a total of 180 cases (11 vaccinated with pH1N1 vaccine only, 21 with TIV and 13 with both) and 139 controls (6 vaccinated with pH1N1 vaccine only, 4 with TIV and 2 with both).

The VE of 2010 southern hemisphere TIV was shown to be 79% (33–93%) while they provided a low VE of pH1N1 vaccine, 47% (–62 to 82%). Possible explanations of the low VE can be: small number of cases and controls; study design; relatively low study quality according to The Newcastle–Ottawa Scale; and lack of control for potential confounders (i.e. socioeconomic status of participants and underlying medical conditions).

Presented by Kevin Yin, PhD candidate, NCIRS

Age-specific prevalence of and risk factors for anal HPV among men who have sex with women and men who have sex with men: the HPV in men (HIM) study

Nyitray AG, Carvalho da Silva RJ, Baggio ML, et al.
Journal of Infectious Diseases 2011;203(1):49-57.
Link to abstract

Approximately 85% of anal cancers in both men and women are associated with persistent HPV infection. Of those that are HPV positive, over 90% are attributable to HPV 16 and 18 which are the HPV types present in both registered HPV vaccines. In recent years the incidence of anal cancer in both men and women has been increasing. This is particularly true in Australia. International studies have estimated that men who have sex with men (MSM) have great than 30-fold higher incidence of anal cancer compared to other men. To gain better understanding of the natural history of anal cancer in males, in particular the increased incidence in MSM, a number of studies have been initiated to assess prevalence, persistence and clearance of anal HPV infection in healthy males. The aim of this published study was to describe the age-specific prevalence of and risk factors for anal HPV infection among men who have sex with women (MSW) and MSM. Men 18–70 years of age with no prior anal cancer, genital warts or STD diagnosis were recruited from Brazil, Mexico and the USA. At enrolment participants completed a questionnaire and an anal swab was taken for HPV DNA extraction and genotyping. Overall, 16% of men who had positive beta-globin samples (n=1,572) had HPV detected in their anal canal. However, when stratified by sexual orientation, anal HPV infection prevalence for any of the 37 HPV types screened for, was nearly four times greater in MSM than MSW. In addition, infection with multiple HPV types was 10 times greater in MSM than MSW. There was also a difference in the age-specific prevalence curves between MSM and MSW, with peak prevalence of anal HPV infection in MSM observed in younger ages (18–24 years) which then declined with increasing age. However, the anal HPV prevalence curve was flat in MSW. The study also identified a number of risk factors for anal HPV infection primarily relating to sexual behaviour. A positive association between anal HPV infection and number of recent male anal sex partners was observed in MSM, but not with MSW. This supports other studies that suggest that additional mechanisms behind anal HPV infection other than receptive anal intercourse must exist.

Presented by Dr Melina Georgousakis, Research Officer, NCIRS

Intussusception risk and health benefits of rotavirus vaccination in Mexico and Brazil

Patel MM, López-Collada VR, Bulhões MM, et al.
New England Journal of Medicine 2011;364(24):2283-92.
Link to abstract

Presented by Associate Professor Kristine Macartney, Deputy Director – Government Programs, NCIRS

Disease-specific adverse events following nonlive vaccines: a paradoxical placebo effect or a nocebo phenomenon?

Okaïs C, Gay C, Seon F, et al.
Vaccine 2011;29(37):6321-6.
Link to abstract

Disease-specific adverse events following immunisation (AEFIs) can occur following live attenuated vaccines. These AEFIs are disease-specific because they are similar to the symptoms of the disease. Inactivated vaccines, excluding antigen inactivation failures, are unlikely to cause the symptoms of the disease for which the vaccines were administered. The objective of this study was to assess whether safety signals could be because of a bias in the spontaneous reporting of disease-specific AEFIs with inactivated vaccines. All AEFIs of Sanofi Pasteur vaccines spontaneously reported from January 2000 to June 2010 and collected in the Sanofi Pasteur MSD pharmacovigilance database in France were analysed for the study. Vaccine–event pairs of interest were identified beforehand and similar adverse events to the diseases that the inactivated vaccines were intended to prevent were selected. The strength of the association and its statistical significance were assessed using reporting odds ratio (OR) and 95% confidence intervals (CIs). From January 2000 to June 2010, there were 33,275 AEFIs in the database. Sixty-seven per cent of cases were non-serious and 33% were serious. The overall AEFI reporting rate was 2.0 per 10,000 doses distributed for the vaccines studied, ranging from 0.7 (flu vaccine) to 20.9 (rabies vaccine). There was preferential reporting of symptoms of the disease against which an inactivated vaccine was administered, generating detectable safety signals. Hepatobiliary disorders (OR = 2.0; 95%CI 1.3–3.0) were significantly associated with hepatitis B vaccine. In addition, non-combined tetanus vaccines were significantly associated with musculoskeletal disorders and trismus and jaw pain; this was not the case with tetanus-combination vaccines. The highest signal intensity was associated with the newest immunisation program (HPV) in France that began in 2007. The study authors reported that the results might be due to a paradoxical placebo effect and/or a nocebo phenomenon. The limitations of this study included small sample sizes and some AEFIs were counted several times, as an individual could have been vaccinated either with a combination vaccine or with several vaccines concomitantly. The authors concluded that recognising this bias and its psychological mechanisms would help minimise the risk of dissemination of incorrect associations that could disrupt an immunisation program.

Presented by Dr Aditi Dey, Manager - Surveillance, NCIRS

Attitudinal and demographic predictors of measles, mumps and rubella (MMR) vaccine acceptance: development and validation of an evidence-based measurement instrument

Brown KF, Shanley R, Cowley NA, et al.
Vaccine 2011;29(8):1700-9.
Link to abstract

Background: MMR vaccine coverage rates of UK children under the age of 5 have been suboptimal in the past decade. Parental attitudes were related to their child’s MMR status; therefore improving these attitudes is central to improving uptake rates. However, no questionnaire has been developed to quantify parental attitudes and establish their links with vaccination status. This study aims to validate an evidence-based measurement instrument to identify the strongest attitudinal predictors of MMR uptake for interventions to target.

Methods: A 20-item cross-sectional self-administered questionnaire with 5-point Likert scale responses was developed and posted to 2,952 parents of children aged 5–18 years identified from the Child Health Information System in London and North-West England. Independent variables included attitudes towards MMR vaccine and demographic factors. The dependent variable was MMR vaccination status.

Results: 535 parents responded and the attitudes measurement instrument was proven to be psychometrically robust: content valid, good/acceptable internal consistency (Cronbach’s alpha = 0.55–0.75 in all scales), test-retest reliability (Pearson’s correlation >0.60–0.80, p<0.01 to <0.001) and construct validity (significant differences between MMR status groups for four scales and 13 individual items). Predictors for both MMR vaccine dose 1 and 2 included: black and minority ethnicity (OR=1.94 [95% CI: 1.15–3.30] and OR=4.15 [2.40–7.19]); positive MMR attitudes (OR=1.63 [1.00–2.66] to OR=1.97 [1.18–1.31]); and positive social attitudes (OR=1.64 [1.23–2.40] to OR=1.72 [1.13-2.38]).

Discussion: The measurement instrument is robust on multiple validity and reliability dimensions, and is appropriate for use in research and practice as a tool for designing and evaluating interventions. Parents appear to act in line with their attitudes towards MMR vaccine. This study indicates populations and attitudes to be prioritised in MMR uptake improvement interventions.

Presented by Ms Maria Chow, Research Assistant, NCIRS

Invasive pneumococcal disease: association between serotype, clinical presentation and lethality

Rodriguez MA, González AV, Gavin MA, et al.
Vaccine 2011;29(34):5740-6.
Link to abstract

Serotype affects many aspects of invasive pneumococcal disease (IPD) epidemiology. Certain serotypes are shown to be independently associated with greater severity of, and mortality due to, IPD. The objective of this study was to describe the epidemiological characteristics of IPD due to the different pneumococcal serotypes and to determine the association of serotypes and host factors with various clinical presentations and mortality due to IPD. All cases of IPD that occurred in the Madrid autonomous region (MAR), one of the 19 administrative divisions of Spain, from 2007 to 2009 (1st to 3rd year following the introduction of 7-valent pneumococcal conjugate vaccine [7vPCV] for all children in the region) were included in the study. In MAR, 7vPCV was given in a 3+1 schedule and the coverage of 7vPCV in children was 94.4% in 2009.

Incidence rates and the serotype distribution are presented for 2,013 cases of IPD. The incidence rate in children under 2 years of age in the study was approximately 50 per 100,000. In comparison, in Australia the incidence rate of IPD in the 2nd year after the introduction of universal 7vPCV was approximately 20 per 100,000 and approximately 80 per 100,000, respectively, in non-Indigenous and Indigenous children. The case fatality rate of IPD of 9% in the study is similar to that in the early post 7vPCV period in Australia. Breakdown by clinical presentation of approx. 60% pneumonia and approx. 9% meningitis is generally similar to that in other developed countries. Over a third of all cases had an underlying medical condition. The commonest serotype overall was 1, followed by 19A and 7F. In comparison, among non- Indigenous Australians the main stand out serotype causing IPD in the post-vaccination period is 19A (approx. 20%) followed by 3, 4 (5–6%) and 7F (approx. 4%). Serotype 19A, one of the six 13v-non-7vPCV types, caused about a quarter of all IPD in children aged <5 years in the study. Over 40% of all IPD among non-Indigenous Australian children aged <5 years was due to 19A in recent years. Further, serotype 19A was less likely than others to cause meningitis. Serotype 3 was significantly associated with a significantly higher risk of death than other serotypes.

The relatively high number of cases of IPD due to serotype 1 in the study is due to cyclical changes; there were similar observations in this population, as well as in other countries in the region, even prior to the introduction of 7vPCV. Substantial herd effect from the childhood 7vPCV program was evident in the study. No cases of vaccine failure were detected. Two partially vaccinated children had IPD due to 19F. The low invasive potential and the high severity of IPD due to serotype 3 has been reported in other studies as well. The comparatively lower risk of death associated with serotypes 1 and 7F in the study is consistent with other studies that report a higher invasive potential and a lower severity of disease with these serotypes compared to others. This study also reports a higher likelihood of IPD due to serotype 8 in those with underlying medical conditions compared to those without such risk factors. In the study, 56 % and 79% of all cases of IPD in all ages and in children aged <5 years, respectively, was caused by 13v-non-7v serotypes. In June 2010, MAR changed over to use 13vPCV in place of 7vPCV in their childhood vaccination program. In children aged <5 years in Australia, 54% of all IPD in 2007–08 was caused by 13v-non-7v serotypes. On 1 July 2011, 13vPCV replaced 7vPCV on the NIP for all children in all jurisdictions in Australia except the Northern Territory. Replacement of 7vPCV with 13vPCV is expected to counter the increasing burden of 13v-non-7v IPD. This study provides a reasonably comprehensive description of epidemiology of IPD in one jurisdiction in Spain in the post-7vPCV era that can be compared and contrasted with that in Australia.

Suggested further reading:
Williams SR, Mernagh PJ, Lee MHT, Tan JT. Changing epidemiology of invasive pneumococcal disease in Australian children after introduction of a 7-valent pneumococcal conjugate vaccine. Medical Journal of Australia 2011;194:116-120.
Weinberger DM, Harboe ZB et al. Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis. Clinical Infectious Diseases 2010;51:692-699.

Presented by Dr Sanjay Jayasinghe, Senior Policy Officer, NCIRS

Q fever epidemiology and control in Australia, and the recent outbreak in The Netherlands

Guest speaker: Dr Heather Gidding
Senior Statistician, Biostatistics and Databases Programs, The Kirby Institute (formerly the National Centre in HIV Epidemiology and Clinical Research), Faculty of Medicine, University of New South Wales

In 2010, Heather attended the inaugural Groningen Vaccination Days meeting where she presented the results of the NCIRS evaluation of Australia’s National Q fever Management Program. Australia is the only country to have introduced Q fever vaccination and our experience with Q fever control was of particular interest to European government and research groups as The Netherlands was in the grip of the largest outbreak of Q fever ever identified.

Heather is an infectious diseases epidemiologist and biostatistician. She currently works at the Kirby Institute (formerly the National Centre in HIV Epidemiology and Clinical Research) as the study coordinator for the Australian Chronic Hepatitis C Observational Study (ACHOS). Her main areas of interest include the use of routinely collected data for epidemiological research, in particular using data linkage methods, and longitudinal data analysis techniques. She recently completed a PhD on hepatitis C associated morbidity and treatment.

Heather gave an overview of the epidemiology and control of Q fever in Australia and the impact of Australia’s National Q fever Management Program, as well as relating Australian control methods to the outbreak in the Netherlands.

Q fever is caused by the bacterial pathogen Coxiella burnetii. Worldwide, C. burnetii infects a wide range of animals; however, in Australia the main sources of infection are cattle and sheep. Humans are infected by contact with the infected animal or animal products usually via inhalation of infected aerosols. In Australia, a majority of Q fever cases are in males, particularly in the 18–24 year age group, which correlates with the age of new workers in the farming/abattoir industry. The majority of cases now, as in the pre-vaccine era, are reported in south western Queensland and northern New South Wales. In the early 1980s, CSL developed an inactive whole cell vaccine against Q fever, which was licensed for use in Australia in 1989. In October 2000, a government funded vaccination program against Q fever was announced, and rolled out in all states except the Northern Territory in 2001–2002. This program had two phases: the first targeting abattoir workers and shearers; the second targeting farmers, their employees and families. Depending on the jurisdiction, the government funded program ceased in all states by June 2007.

An evaluation of the Q fever program carried out by NCIRS identified a number of strengths. Overall, the program increased awareness for the vaccine and the capacity to deliver it. This resulted in an estimated national coverage among the target group of 50–54% and, in turn, a dramatic and targeted decline in Q fever notification rates was observed in the years following the introduction of the program. In 2010, Heather presented the results of the NCIRS evaluation of Australia’s National Q fever Management Program at the inaugural Groningen Vaccination Days meeting in The Netherlands, which was convened in response to the largest Q fever outbreak ever reported. This outbreak was first identified in farm animals and then in humans in the following years, with more than 2,300 human cases reported in 2009. Q fever incidence rates were highest in areas that had the highest density of goat farms. In response to this outbreak a number of control measures were introduced both in the animal population and also in humans. In comparison to what has been seen in The Netherlands, in Australia there is a higher proportion of Q fever cases among males, no seasonality with Q fever notifications is apparent, and Q fever seems to be restricted to high risk workers, whereas in The Netherlands it seems to be a community wide issue.

Based on the situation in Australia and in Holland, Heather recommended a number of key factors important for the control of Q fever including both animal and human Q fever surveillance, continuing education campaigns for at-risk groups and providers, and enhanced Q fever notification data.

A brief introduction to meningococcal disease, meningococcal vaccines and a recent paper on the immunogenicity and safety of PsA-TT: Immunogenicity and safety of a meningococcal A conjugate vaccine in Africans

Sow SO, Okoko BJ, Diallo A, et al.
New England Journal of Medicine 2011;364(24):2293-304.
Link to abstract

Meningococcal disease is one of the most severe infections with a mortality up to 10% despite appropriate antibiotic treatment. The disease is caused by the bacterium Neisseria meningitidis which is classified into 13 serogroups. Globally, serogroups A, B, C, W135 and Y are most common. Neisseria meningitidis can cause meningitis with/without septicaemia and also some other local infections, such as pneumonia and arthritis. N. meningitidis is carried and transmitted (through respiratory droplets) only by humans.

Meningococcal disease can be sporadic or epidemic. Serogroup A disease occurs mainly in developing countries with serogroup B and C in developed countries. The majority of meningococcal disease occurs in those <5 years of age. Meningococcal vaccines can be divided into the meningococcal C conjugate vaccines (MenCCV) and the tetravalent meningococcal polysaccharide vaccines (4vMenPV).

Sow SO et al. (N Engl J Med 2011;364:2293-304) evaluated the immunogenicity and safety of an affordable, highly immunogenic meningococcal A conjugate vaccine – PsA-TT – in Africans through two studies. Study A included 601 children aged 1 year using PsA-TT, a reference vaccine (PsACWY) and a control vaccine (Haemophilus influenzae type b conjugate vaccine). Study B enrolled 900 subjects aged 2–29 years with two-thirds of participants receiving PsA-TT while the other third were given PsACWY. The endpoints of measurement were immunogenicity (seroconversion and IgG specific antibody titre) and vaccine associated adverse events. Both studies reported a (very good and) higher immune response of PsA-TT compared to PsACWY. The new vaccine seemed to be generally well tolerated with increased risk of tenderness and induration at injection sites.

Presented by Dr Kevin Yin, Research Officer, NCIRS

The prevalence of hepatitis B virus infection in the United States in the era of vaccination

Wasley A, Kruszon-Moran D, Kuhnert W, et al.
Journal of Infectious Diseases 2010;202(2):192-201.
Link to abstract

The purpose of this study was to compare the prevalence of hepatitis B virus (HBV) infection before and after the introduction of vaccination in the USA and also to report on the prevalence of vaccine induced immunity among non-institutionalised US residents. Data from the National Health and Nutrition Examination Surveys (NHANES) were analysed. A major reduction in the prevalence of HBV infection was observed in children, across two time periods (1999–2006 and 1988–1994), particularly among children who were born outside the USA. Prevalence remained unchanged among adults. Vaccine induced immunity was lower among older persons.

This paper is particularly important from a health disparities/equity point of view, as it clearly demonstrates a reduction in the difference in prevalence rates between US and foreign born children, across the two time periods. The results are also indicative of the relative success of HBV infection prevention programs, globally, targeting children. Results similar to these can be expected in the Australian setting. Prevalence rates for vaccine induced immunity among children and adolescents in this study were similar to those reported by Gidding et al. (2007) for Australian children and adolescents.

Presented by Dr Bradley Christian, Research Assistant, NCIRS

Longitudinal predictors of human papillomavirus vaccine initiation among adolescent girls in a high-risk geographic area

Brewer NT, Gottlieb SL, Reiter PL, et al.
Sexually Transmitted Diseases 2011;38(3):197-204.
Link to abstract

This study aimed to identify what factors predict uptake of HPV vaccination among adolescents at risk. The study was conducted in five US counties where women are at increased risk of cervical cancer because of their ethnicity and where they live (rural areas). Caregivers, mostly parents, of adolescents aged 10–18 were interviewed twice by phone. The second interview was approximately a year after the first.

Parents who indicated that they had not had their daughters vaccinated against HPV on the first call were asked about their daughters' vaccination status on the second interview. Twenty-seven per cent of the daughters had started the HPV vaccination course at the time of the second interview. Intention to get the vaccine was related to vaccination, as was not being a born-again Christian.

Some other factors associated with vaccination were lowered perceived barriers to getting the vaccine, greater anticipated regret if their daughters contracted HPV, and parents who did not originally state that they needed more information. This last result is related to the Australian context, because we have findings that indicate some parents want more information before making a decision about HPV vaccination. We don't have longitudinal data linking that need to vaccination uptake, but this finding indicates that they could be related. Designing more in-depth materials for parents and adolescents should be a priority.

Brewer and colleagues concluded that, since many unvaccinated girls had attended a physician visit in the past year, there were many missed opportunities of physicians recommending vaccination. They also noted that anticipated regret may be a method of convincing parents to vaccinate their daughters.

Presented by Dr Spring Chenoa Cooper Robbins, Postdoctoral Researcher, Sydney University Paediatrics & Child Health and NCIRS

New vaccines for tuberculosis

Kaufmann SH, Hussey G, Lambert PH.
Lancet 2010;375(9731):2110-19.
Link to abstract

This article examines the present and the future for vaccines against Mycobacterium tuberculosis (TB). The current BCG vaccine is safe and relatively cheap but only provides protection for infants. Unfortunately, HIV-infected infants are at higher risk of disseminated BCG disease so BCG vaccine should not be used in this vulnerable group. BCG in adults has limited effectiveness. Therefore a number of potential TB vaccine candidates are being evaluated. To develop such a vaccine, the pathogenesis of TB also needs to be understood so that the mechanism of TB vaccine candidates can stimulate the anti-mycobacterial immune response.

The strategies being used include enhancing the use of the existing BCG vaccine in conjunction with additional vaccines, or replacing the BCG vaccine with newer vaccines. Live TB vaccines can be based on either improving the current BCG by adding other genes to it or by deleting genes and attenuating the strain. Another avenue is through the use of a suitable vector in which subunits of relevant TB genes are recombined. Vaccines that actually enhance the TB chemotherapy are also being investigated. Two potential candidates, one using whole-cell killed Mycobacterium vaccae and the other based on fragments of mycobacteria, are currently being assessed.

The other critical issue is trials of the new TB vaccines. Often such trials occur in poorer developing countries where regulatory requirements are sometimes poor at best. This also means that informed consent can be difficult to achieve where people’s literacy levels are low, people are research naïve and poverty is endemic. Another issue with TB vaccine research is that there is no well-defined surrogate for clinical protection against TB so efficacy studies are difficult. Laboratory identification or confirmation of TB is often confined to smear diagnosis alone. Regional capabilities also need to be assessed and strong partnerships formed.

There are a number of issues with fulfilling the aims of halving TB prevalence and mortality by 2015 and reaching the target of fewer than one new tuberculosis case per million population by 2050. At least USD $2 billion is required to fund research and development of TB vaccines over the next 10 years.

Presented by Dr Jane Jelfs, Manager, Policy Support, NCIRS

Attitudes and beliefs of parents concerned about vaccines: impact of timing of immunization information

Vannice KS, Salmon DA, Shui I, et al.
Pediatrics 2011;127(Suppl 1):S120-6.
Link to abstract

This study aimed to determine if giving vaccine information materials (vaccine information statements [VIS] + a new vaccine information pamphlet) before the initial (2-month) vaccination visit to mothers with concerns about vaccine safety positively changed their attitudes and beliefs about vaccine safety.

Following initial screening, 272 mothers who indicated concerns about infant vaccinations were given vaccine information either during a prenatal visit; a 1-week postpartum well-child visit; or a 2-month vaccination visit. In addition, a separate group of concerned mothers were given information at each of these time points and was analysed separately. Attitudes and beliefs about five questions on vaccine safety were assessed both before and after the review of materials and preferences for timing of receipt of materials were sought.

After reviewing the vaccine information materials, mothers in all groups showed improved attitudes to statements supporting the safety and importance of vaccines. More than 95% of the participants reported a preference for receiving vaccine information materials either during pregnancy or at a well-child visit before the initial (2-month) vaccination visit. However, results did not show significant improvement in attitudes in the prenatal or 1-week groups compared to the 2-month reference group after controlling for a variety of factors. This may have been an artefact of the study design which allowed mothers quite a bit of time to read the materials prior to the 2-month visit; this may have diluted the benefit of providing the materials at earlier visits.

The authors concluded that vaccine information materials should ideally be provided before the initial vaccination visit or offered at all prenatal visits to accommodate different parental preferences. Parents/guardians should also be given sufficient time to review these materials, even if done at the vaccine visit.

Presented by Kirsten Ward, Immunisation Programs Evaluation Program Officer, NCIRS

Decline in diarrhea mortality and admissions after routine childhood rotavirus immunization in Brazil: a time-series analysis

do Carmo GM, Yen C, Cortes J, et al.
PLoS Medicine 2011;8(4):e1001024.
Link to article

The impact of the monovalent G1P[8] strain human rotavirus vaccine was assessed in Brazil where universal infant vaccination was introduced in 2006. The investigators interrogated national databases on mortality (from death certificates) and hospitalisations (hospitalisation database covering most public hospitals) over the pre (2002–2005) and post (2007–2009) vaccine periods across each of five regions. Vaccine coverage was estimated to vary from 65% to 86% across the regions. The incidences of expected diarrhoea-related deaths and admissions were modelled from the pre-vaccine data adjusting for both seasonal and secular trends. There was a significant year-by-year decline in deaths and hospitalisations in the pre-vaccine era, especially in the <12 month age group (13% per year for deaths, 7% per year for admissions). Even adjusting for this, deaths were significantly lower than expected in the vaccine years (22% lower for deaths and 17% lower for admissions). Reductions were greatest in the <2 year age group for whom vaccine coverage was highest and in the north and northeast where socioeconomic conditions are worst and infant mortality is highest. Albeit limited by being purely ecological, the study adds to the demonstration of similar reductions in mortality demonstrated in Mexico.

Presented by Dr Tom Snelling, Senior Clinical Fellow, NCIRS

Rabies in travellers

Most rabies cases occur in the developing regions of Africa and Asia, and are transmitted by stray and domestic dogs. Other areas of concern are India, Thailand, Bali, Indonesia and Vietnam. Rabies is now enzoonotic in Bali and numbers of travellers to Bali from Australia are increasing rapidly.
Duration of travel is often under 30 days in those with a significant rabies exposure, despite guidelines recommending pre-exposure prophylaxis (PrEP) in those travelling for more than 30 days.

Many travellers do not receive formal travel advice. Even when they do, it is not being offered appropriately or taken up well. Promoting PrEP knowledge among travellers and travel medicine practitioners may reduce need for post-exposure prophylaxis (PEP) or rabies immunoglobulin (RIG).

Studies addressing the knowledge and perception of rabies risk in travellers all demonstrated a low awareness of rabies risk among travellers, particularly among ex-pat travellers.

PEP is not effectively administered overseas and PrEP is not always extensively utilised by travellers. RIG is often unavailable overseas. Most travellers who present post bite to medical clinics are missing out on both PrEP at home and PEP in the country of bite, resulting in a delayed regimen commencement on return home.

Even highly immunogenic 8-site intradermal regimens or double dose 2-site ID regimens (TRC) do not obviate the need for RIG in countries where RIG is not readily available.

Some studies indicate that application of the WHO guidelines is suboptimal even in developed countries. As well as the WHO guideline, the following are also widely recommended:
- Avoid contact with wild animals and unknown domestic animals, particularly stray dogs and cats.
- Thoroughly wash for 15 minutes any animal wounds (soap, water, virucidal agents such as povidone/iodine).
- Seek medical assistance urgently.
- Cell culture vaccine and RIG may need to be purchased from private pharmacies.
- Request a PEP certificate from the vaccination centre and record.
- Disregard vaccination status of animal and, in a dog rabies-infected country, the health status of the animal.
- Do not wait for the results of animal observation periods before initiating prophylaxis.
- Be aware that the streets of big-city slums where dogs roam wild carry a moderate risk, whereas those who visit tourist resorts are at very low risk.
- Receive preventive immunisation when the travel involves a significant risk of exposure or when it is to a rabies-infected area where modern rabies vaccine and immunoglobulin may not be available.

Travellers most often present for PEP from Indonesia, especially from Bali. A study of 42 patients who were returned travellers seeking PEP from Bali revealed that most were bitten by macaque monkeys, found in monkey temples, not dogs. Monkey attacks can be avoided by not approaching monkeys, not carrying food and not paying particular attention to baby monkeys.

The probability of being bitten or scratched by a susceptible animal species, usually a dog or a cat, depends on density and confinement of the animals, the traveller’s travel plans (urban/rural/trekking), and the traveller’s behaviour towards animals. It is empirically considered that dog rabies will not persist if the dog population density is below 4.5 dogs per square kilometre.

Travellers need to be aware of how best to access vaccines in the areas in which they travel. In many developing countries, modern safe effective cell culture rabies vaccines are available only in major urban centres or capital cities. Some countries import cell culture vaccines which are available at peripheral health delivery level. In some parts of India, the country with the highest reported number of cases of rabies, some government centres still dispense nerve tissue vaccines to up to half a million people a year. Some countries in Africa (e.g. Madagascar) have switched to modern vaccines but in other countries (Algeria, Senegal) nerve tissue vaccine production capabilities persist.
Some countries such as Sri Lanka and the Philippines have secured regular supply of RIG and Thailand is making its own equine rabies immunoglobulin (ERIG). In most developing countries availability is sporadic and limited as RIG is in short supply due to production being generally limited to a few companies globally. Pre-exposure prophylaxis for travellers can enable them to avert this problem as RIG is not needed for PEP if pre-vaccinated.

WHO promotes the increased production and use of highly purified horse immunoglobulins.

Presented by Dr Rashmi Dixit, Senior Clinical Fellow, NCIRS

Maternal influenza vaccination and effect on influenza virus infection in young infants

Eick AA, Uyeki TM, Klimov A, et al.
Archives of Pediatrics & Adolescent Medicine 2011;165(2):104-11.
Link to abstract

Influenza infection is often a cause for hospitalisation or primary care visits for children under 5 years of age. Children with underlying medical conditions are hospitalised approximately four times more often than healthy children and, during severe influenza seasons, infants 0-6 months of age are generally more affected than those 6–12 months old.

Due to the increased risk due to influenza disease during pregnancy the United States recommends seasonal influenza vaccination for all pregnant women. Influenza vaccination for pregnant women may also provide benefits for their unborn infant who will not be able to receive vaccination until 6 months of age.

Various studies have looked at the benefits of maternal vaccination to protect young infants from influenza disease or severity post-delivery. This study followed three influenza seasons during 2002–2005 and included mothers who reached at least 36 weeks gestation and gave birth to a healthy infant who was recruited at less than 2 weeks of age.

Historically Navajo and White Apache Mountain Indian children experience higher levels of acute respiratory disease than other American children prompting the study researchers to recruit mother-infant pairs from Indian Health Services from Navajo and White Apache Mountain Indian Reservations.

The aim of this study was to compare the influenza disease burden in infants whose mothers were vaccinated with seasonal influenza vaccine with the burden in infants whose mothers were unvaccinated. Eight influenza strains that were identified during the three influenza seasons were investigated.

There were 193 (17%) infants hospitalised with influenza-like illness (ILI) and 412 (36%) infants who only had one ILI-related outpatient visit; 555 (48%) had no reported incidence of ILI. This study showed a 41% reduction in laboratory-confirmed influenza infection risk in infants born to influenza-vaccinated women compared with infants born to unvaccinated mothers.

Limitations stated by the study researchers included that ‘research was conducted over relatively mild influenza seasons’ and there was the possibility that mother-infant demographics may have confounded findings.

Presented by Telphia Joseph, National Indigenous Immunisation Coordinator, NCIRS

Internet-based reporting to the Vaccine Adverse Event Reporting System: a more timely and complete way for providers to support vaccine safety

Haber P, Iskander J, Walton K, et al.
Pediatrics 2011;127(Suppl 1):S39-44.
Link to abstract

The Vaccine Adverse Events Reporting System (VAERS) was created in the USA in 1990 under the joint administration of the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA). Its unique role as a national spontaneous reporting system enables the early detection of potential vaccine safety concerns.

Internet-based reports (IBRs) were added to VAERS in 2002 to allow rapid, expedited reporting of adverse events (AEs) in anticipation of wider use of counter-bioterrorism vaccines such as those against smallpox and anthrax.

The aim of this study was to evaluate the impact of IBRs on the timeliness and completeness of vaccine adverse event reporting.

The study demonstrated that IBRs are more timely and complete and therefore provide an important improvement to VAERS when compared with the traditional paper-based reports. A shorter reporting interval provides a better chance for timely detection of serious or life-threatening events and, consequently, timely public health intervention. Completeness of the report is critical to the validity of VAERS reports which can provide important information on the biological plausibility of the reported AEs being associated with the administered vaccine. It has also been shown that IBRs have the potential to reduce transcription and data-entry errors and result in more accurate data.

However, there is a need for additional improvements of electronic messaging to VAERS including acceptance of data from electronic medical records and acceptance of selected information from immunisation information systems (IIS) or immunisation registries. Such improvements will enable vaccine providers to record and report AEs directly to VAERS by using their current electronic IIS or vaccine registries and further increase efficiency and completeness of electronically submitted VAERS reports.

Knowledge and use of secure web-based vaccine AEs reporting should become part of the well-informed clinician’s vaccine-safety toolkit. More information and reporting resources are available at www.vaers.hhs.gov

Presented by Dr Deepika Mahajan, Senior Research Officer, NCIRS

Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels

Gall SA, Myers J, Pichichero M.
American Journal of Obstetrics & Gynecology 2011;204(4):334,e1-5.
Link to abstract

and

Effect of a prepregnancy pertussis booster dose on maternal antibody titers in young infants

Leuridan E, Hens N, Peeters N, et al.
Pediatric Infectious Disease Journal 2011 January 4 [Epub ahead of print].
Link to abstract

Very young unimmunised infants are most at risk of severe disease and death from pertussis. Parents have been identified as an important source of infection in these infants. The currently recommended strategy to deal with this is ‘cocooning’ the infant by vaccinating adult close contacts. Studies are also being conducted to investigate the use of a birth dose of pertussis vaccine. Another area of study is maternal immunisation, which could allow the passive transfer of antibodies to infants across the placenta and avoid any delay in vaccinating the mother post partum. Both of these studies demonstrate the successful transfer of antibodies against pertussis vaccine antigens to newborns, following vaccination of mothers both pre-pregnancy and during pregnancy. However, there are still several questions that need to be addressed by further study. It is unclear what amount of antibodies is enough, particularly as they appear to decay rapidly and ideally they would need to be protective until the first dose of vaccine is given to the infant at 2 months of age. It is unclear how long after vaccination of the mother antibody transfer will occur, and if re-administration of vaccine would be required, and how often. It will also be important to ensure that there is no interference from maternal antibodies, when the infant is being immunised, particularly if a birth dose of vaccine does become available.

Presented by Dr Helen Quinn, Research Fellow, NCIRS

Impact of the national rotavirus immunisation program

Aditi Dey, Han Wang, Kirsten Ward, Rob Menzies, Kristine Macartney
National Centre for Immunisation Research and Surveillance

Rotavirus is a leading cause of hospitalisation for acute gastroenteritis in Australia, particularly for those under 5 years of age. The national rotavirus immunisation program commenced in July 2007. The aim of this study was to examine differences in national hospitalisation rates of rotavirus and non-rotavirus gastroenteritis before and after vaccine introduction.

National Hospital Morbidity data (AIHW) and population data were used to calculate age-specific hospitalisation rates for rotavirus (ICD-10-AM code of A08.0) and non-rotavirus gastroenteritis (ICD-10-AM codes K52 and A01 to A09 excluding A08.0) with separation dates between 31 July 2001 and 30 June 2009. A 70.8% decline in rotavirus hospitalisations in children <5 years of age was observed from 261.2 per 100,000 in July 2001 to June 2006 to 76.4 per 100,000 in July 2008 to June 2009. Simultaneously, a 33.9% decline in non-rotavirus hospitalisations in children <5 years of age was observed from 1419.2 per 100,000 to 937.5 per 100,000 in the same time period. A reduction was also observed in the 5–19 year age group indicating a herd immunity effect. These data suggest an immediate and substantial decline in severe rotavirus disease and all-cause acute gastroenteritis since the introduction of rotavirus vaccination.

Presented by Dr Aditi Dey, Manager - Surveillance, NCIRS

Impact of conjugate 7-valent vaccination in Belgium: addressing methodological challenges

Hanqueta G, Lernouta T, Vergisond A, et al.
Vaccine 2011;29(16):2856–64.
Link to abstract

This article reported on the early impact of the national 7-valent pneumococcal conjugate vaccine (7vPCV) program for children in Belgium on the incidence of invasive pneumococcal disease (IPD) in children aged <5 years, in particular children aged <2 years. The “2+1” schedule was implemented by the national program since January 2007 with a catch-up component for children aged <2 years, but the '3+1' schedule was used when 7vPCV was available in the private market prior to 2007. IPD incidence was estimated through the national reference laboratory and active surveillance through reporting by paediatricians, with under-estimates adjusted for by the capture-recapture method. With the classical model that assumed constant incidence rate before vaccine implementation, 2 years since the implementation of the universal infant 7vPCV program (when vaccine uptake was estimated to be about 80–100%), the incidence rate of IPD overall decreased by 37%, and the rate of IPD due to 7vPCV serotypes by 96% in children aged <2 years. For children aged 2–4 years, although the rate of IPD due to 7vPCV serotypes decreased by 76%, the overall rate increased by 33% as a result of a substantial increase in the rate of IPD due to non-7vPCV serotypes. Pneumococcal meningitis due to non-7vPCV serotypes increased among children aged <2 years, and there was an increase in non-vaccine type pneumonia in both age groups and an increase in invasive pneumonia in the 2–4 year age group. An increasing secular trend of some non-7vPCV serotypes (e.g. serotypes 1 and 19A) was observed prior to the universal vaccination program. If a linear regression model is fitted to the pre-program data, the estimated impact of increase in IPD due to non-7vPCV serotypes will be less compared to the model with a constant rate assumption.

A similar pattern of early impact on IPD incidence in young children has been seen in a number of countries, where different schedules and program configurations were implemented. This article is one of the reports of 7vPCV program impact where more comprehensive analysis by small age group, clinical syndrome, serotype groups and individual serotypes have been undertaken, in association with estimated vaccine uptake and antibiotic susceptibility trends. However, there are certain methodological issues that may render interpretation of these data difficult, including the use of proportional distribution to adjust for missing data across different time periods, their method of estimating true incidence by capture-recapture, arbitrary assumption of a linear regression model for adjustment of pre-program trend, particularly when analysing trend by serotypes in aggregate (which implicitly assumed a uniform trend for different serotypes), and limitations in obtaining reliable vaccine uptake data.

Presented by Dr Clayton Chiu, Public Health Physician - Policy & Surveillance, NCIRS

Tracking parental attitudes on vaccination across European countries: the Vaccine Safety, Attitudes, Training and Communication Project (VACSATC)

Stefanoff P, Mamelund SE, Robinson M, et al.
Vaccine 2010;28(35):5731-7.
Link to abstract

The Vaccine, Safety, Attitudes, Training and Communication Project (VACSATC) was a project involving mainly public health experts from 14 countries across Europe. The group agreed on a common thematic approach to monitor vaccination cross the 14 countries. Each country conducted a survey between 2007 and 2009, which was based on a standard list of 10 core questions. This paper summarises the results of the surveys conducted in England, Norway, Poland, Spain and Sweden, with a view to assessing the possibility of a standard survey that could be applied across geographic and cultural barriers.

While each country used a survey based on the same 10 core questions, the surveys delivered in the respective countries differed in some of the questions, as did the method of sampling and recruitment. Despite these differences, some results were reported across all countries, including the fact that most people saw vaccination as a good thing, most people recognised the benefits of herd immunity, and that healthcare professionals were the most consulted and trusted source of information regarding vaccination. Differences between the countries included the number of people expressing doubt about vaccines and their reasons for doing so, and the perceived comparative seriousness of specific vaccine preventable diseases.

It was concluded that a standard multinational survey with a large number of questions could not be achieved, due to resource constraints and inapplicability of some questions to some regions. However, the authors saw the survey as a “move towards a shared understanding of the importance of polling public opinion”, and indicated that this work should continue in order to allow comparability of certain indicators between countries, and to also monitor changes in parental attitudes to vaccination.

Presented by Kerrie Wiley, Research Assistant – Social Research, NCIRS

The predicted impact of HPV vaccination on male infections and male HPV-related cancers in Australia

Smith MA, Lew JB, Walker RJ, et al.
Vaccine 2011 March 17 [Epub ahead of print].
Link to abstract

The current Australian national HPV vaccination program provides ongoing vaccination of girls 12–13 years of age against HPV. This study used a dynamic model of sexual behaviour and HPV transmission to estimate the incremental benefits to males if they were included in the vaccination program, above and beyond what is already being achieved through the current female program. To address this aim the authors estimated vaccination coverage currently achieved in females and expected to be achieved in males, as well as HPV prevalence in females and males due to heterosexual transmission prior to the introduction of the vaccination program. They then modelled the short- and long-term impact of the female only versus gender neutral vaccination program. Based on baseline parameters, the model predicted that the current female program will result in significant reductions in HPV16 infections and associated disease in males by 2050. They estimated that up to three-quarters of the maximum possible vaccination conferred benefit to males will be achieved through the existing female only program. This study did not take into account homosexual transmission of HPV among males, and, in turn, may have over-estimated the number of male HPV-associated cancers adverted by the female only program.

Presented by Dr Melina Georgousakis, Research Officer, NCIRS

Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease

Tseng HF, Smith N, Harpaz R, et al.
JAMA 2011;305(2):160-6.
Link to abstract

This paper reports the results of a large observational study among community-dwelling adults aged 60 years or older evaluating the risk of herpes zoster after herpes zoster vaccination in a managed care organisation.

The study was done with a fully insured population in one region of the USA; therefore, the results need to be generalised carefully. The study was also not designed to assess severity or duration of symptoms among HZ cases or to assess the effectiveness of HZ vaccine at preventing post-herpetic neuralgia. The average length of follow-up was short and not designed to capture any decline in protection that is likely to occur with time. The study also could not control for family history of herpes zoster, which could predispose family members to herpes zoster or encourage them to seek vaccination.

Among study participants, receipt of the herpes zoster vaccine was associated with a lower incidence of herpes zoster, among all age strata and among individuals with chronic diseases. Herpes zoster vaccine was licensed recently, which means the durability of its protection needs to be assessed in future studies. To date, herpes zoster vaccine uptake has been poor due to weaknesses in the adult vaccine infrastructure and also due to serious barriers to the vaccine among clinicians and patients.

Presented by Brynley Hull, Epidemiologist, NCIRS

Global collaborative network for vaccine safety studies – a report on a recent conference

Link to conference program

The Global Collaborative Network for Vaccine Safety Studies met in Annecy, France, in March 2011. The attendees included academics from Europe, USA and Australia, representatives from regulatory authorities and the pharmaceutical industry, and members for lower to middle income countries. There was a recognition of the benefits of collaborative studies to investigate safety signals around the world, particularly given the rare occurrence of some adverse events and population size in individual countries. There was also a recognition of the difficulties in trying to combine data from separate countries. Successful examples include the VAESCO consortium funded by the European CDC and others. VAESCO is the Vaccine Adverse Events Consortium, a group of investigators across most of Europe which has collaborated to examine whether there is an increased risk of Guillain-Barré syndrome or narcolepsy after H1N1 vaccine. Results are yet to be finalised but early data suggests there is no link with GBS. Another successful example was the examination of intussusception and rotavirus in Mexico and Brazil which suggested an increased risk of 1 in 50,000 to 76,000 vaccines. WHO has also set up a collaborative study, involving Australia, to look at H1N1 and the link to GBS in countries outside of Europe as well as combining data with VAESCO. These initiatives demonstrate that it is feasible to set up and run collaborative studies across different countries. Much work needs to be done in lower to middle income countries where less data is available and infrastructure is not as well developed.

Presented by Dr Nick Wood, Senior Clinical Research Fellow, NCIRS

Detection of rotavirus antigenemia in routinely obtained serum specimens to augment surveillance and vaccine effectiveness evaluations

Patel M, Rench MA, Boom JA, et al.
Pediatric Infectious Disease Journal 2010;29(9):836-9.
Link to abstract

Globally, rotavirus is a major cause of severe acute gastroenteritis in children. This study explored whether sera or plasma obtained from children suffering from severe acute gastroenteritis in usual clinical practice could supplement faecal specimen testing in surveillance of rotavirus disease. This case-control study determined the diagnostic validity of antigenemia using enzyme-linked immunosorbent assay (EIA) in identifying rotavirus infection. In addition, the study compared vaccine effectiveness (VE) using cases identified by serum/plasma testing versus stool testing. The study found that rotavirus antigenemia is a relatively sensitive (76%), highly specific (95%), and predictive marker of rotavirus disease. However, there was a slightly lower rotavirus detection rate in serum/plasma compared with stool. The 3-dose vaccine effectiveness was similar in cases identified by serum/plasma (VE 84%; 95% CI 25%–96%) to cases identified though faecal specimen testing (VE 85%; 95% CI 55%–95%). Though the results are promising they should be interpreted cautiously as the available rotavirus EIAs are intended to detect rotavirus antigen in faecal specimens and have not been validated in large studies for serum/plasma samples and are affected by several factors including number of days between acute gastroenteritis onset and serum or plasma collection.

Presented by Dr Aditi Dey, Manager Surveillance, NCIRS

Trends in anal cancer in Australia, 1982–2005

Jin F, Stein AN, Conway EL, et al.
Vaccine 2011;29(12):2322-7.
Link to abstract

Human papillomavirus (HPV) is causally associated with anal squamous cell carcinoma (SCC). About 80% of cases of anal cancer are associated with those high risk types covered by the currently available bivalent and quadrivalent HPV vaccines. Recently the quadrivalent HPV vaccine was shown to be efficacious against HPV 6/11/16/18-related anal dysplasia in a population of men who have sex with men (MSM). Adenocarcinoma, the other common histological type of anal carcinoma, is not known to be associated with HPV infection.

Similar to most other comparable populations, in Australia anal cancer is a relatively rare malignancy with an incidence of less than 2 per 100,000 in the general population. An increasing trend of this cancer is reported from the UK and the USA in the last few decades. Little is known about the burden of HPV attributable anal dysplasia and anal cancer in Australia. This paper describes the trends in the burden of disease and the 5-year survival of anal cancer in Australia, from 1982 to 2005, using data from the national cancer statistics clearing house of the Australian Institute of Health and Welfare. Such information is useful to monitor the impact on anal cancer of the existing HPV vaccination program for females, and to estimate the benefits of extending the vaccination program to include all adolescent boys or other subgroups with a high risk of HPV infection.

The total number of all invasive anal cancers that occurred from 1982 to 2005 in Australia was 4,615 cases. The annual average number of cases in 1982–1987 of 118 has more than doubled to 271 in 2000–2005. Rates of anal SCC have consistently remained higher in females than in males, but, with the average annual increase in males being almost 2-fold that of females, rates are converging. The increase in the incidence of SCC was much steeper than adenocarcinoma. There has also been a concurrent increase in the 5-year survival of anal SCC by 10%.

Men who have sex with men, women with a history of HPV-associated high grade cervical dysplasia and those immunocompromised due to disease or treatment are at increased risk of HPV-associated anal cancer. The study postulates that increases in anal SCC could be related to increasing prevalence of homosexual male behaviour, a trend towards earlier age of sexual debut, and a higher number of life-time sexual partners. If HPV vaccines are prophylactic against high grade anal dysplasia among other population groups as it is in MSM, a likely decline in anal SCC in females would occur as a direct effect of the current HPV vaccination program. However, MSM would have very little protection against anal dysplasia from the existing HPV vaccination program. Identifying persons with high risk of HPV infection prior to their sexual debut for a targeted vaccination program would be a major challenge. Further research on anal cancer in Australia is needed to guide policies regarding anal cancer prevention strategies including vaccination.

Presented by Dr Sanjay Jayasinghe, Senior Policy Officer, NCIRS

Pneumococcal meningitis in French children before and after the introduction of pneumococcal conjugate vaccine

Levy C, Varon E, Bingen E, et al.
Pediatric Infectious Disease Journal 2011;30(2):168-70.
Link to abstract

Presented by Dr Alexa Dierig, Clinical Research Fellow, NCIRS

Post-licensure monitoring of HPV vaccine in the United States

Markowitz LE, Hariri S, Unger ER, et al.
Vaccine 2010;28(30):4731-7.
Link to abstract

and

Monitoring the control of human papillomavirus (HPV) infection and related diseases in Australia: towards a national HPV surveillance strategy

Brotherton JM, Kaldor JM, Garland SM.
Sexual Health 2010; 7(3):310-9.
Link to abstract

Post-licensure evaluation of vaccines plays an important role in monitoring the progress of immunisation programs, demonstrating population impact of vaccines, and providing data for ongoing policy decisions. Both the USA and Australia licensed a quadrivalent and a bivalent HPV vaccine. In Australia, the national HPV vaccination program began in April 2007 for females aged 12–26 years. The post-licensure monitoring of HPV vaccines in the USA and Australia consists of the following areas: vaccine coverage; provider practices and parental attitudes; vaccine safety; HPV-associated cancer incidence and mortality; genital wart incidence; type-specific HPV infection surveillance; cervical cytology (Pap screening) coverage and screen detected lesion prevalence. Australia has well-established infrastructure such as the National HPV Vaccine Program Register (NHVPR) and Pap screening clinics. However, the asymptomatic and transient nature of HPV makes monitoring difficult. Also, it will take decades before the impact of vaccination on cervical cancer can be observed. Despite the challenges, this type of surveillance approach is valuable should the HPV vaccination program be expanded to males in the future.

Presented by Maria Chow, Research Assistant, NCIRS

Seasonal influenza vaccination campaigns for health care personnel: systematic review

Lam PP, Chambers LW, MacDougall DM, McCarthy AE.
Canadian Medical Association Journal 2010;182(12):E542-8.
Link to abstract

This study was a systematic review of published studies examining interventions to increase influenza vaccination uptake among healthcare workers (HCW). It was undertaken against a background of persistently low influenza vaccination rates, worldwide, despite the availability of vaccine and some evidence of impact on patient outcomes. The authors examined papers published prior to 2009 in a range of databases using the search terms “healthcare personnel”, “influenza vaccine”, and “health facilities”. Studies were selected if they reported organised efforts to promote influenza vaccination among staff and reported the percentage or number of HCW vaccinated as an outcome. They included individual or cluster randomised controlled trials; controlled before-and-after studies with >=1 comparison; and interrupted time series designs with a minimum 5 pre-intervention observations.

Of 3,302 citations, 99 reported organised efforts to increase coverage but only 12 met study design criteria. These were published in the USA, Canada, the UK, Germany and Switzerland between 1992 and 2009 and included long-term care facilities, hospitals and primary health care settings.

In all settings the most common interventions were education or promotion and interventions to improve access to vaccine. None reached 90% uptake. With education or promotion alone or improving access alone, there were small improvements. Legislation or regulatory components (e.g. mandatory declination, mandatory masks) resulted in higher rates than other interventions. Generally, the more components an intervention had, the greater the relative increase in coverage.

The authors encouraged organisations to monitor and report annual vaccination rates for HCW over time, to improve the accuracy of observed outcomes and to provide multiple observation points for an interrupted time series design. They recommend rigorously designed studies assessing the effect of various campaign components.

Presented by Dr Julie Leask, Manager Social Research, NCIRS

AS03A-adjuvanted influenza A (H1N1) 2009 vaccine for adults up to 85 years of age

Roman F, Vaman T, Kafeja F, et al.
Clinical Infectious Diseases 2010;51(6):668-77.
Link to abstract

[Including brief discussion of relevant aspects of two NCIRS publications:
Immunogenicity and safety of pandemic influenza A (H1N1) 2009 vaccine: systematic review and meta-analysis. Yin JK, Khandaker G, Rashid H, Heron L, Ridda I, Booy R. Influenza and Other Respiratory Viruses. 2011; In press.
Cross-reacting antibodies against the pandemic (H1N1) 2009 influenza virus in older Australians. Booy R, Khandaker G, Heron L, Yin JK, Doyle B, Tudo K, et al. Medical Journal of Australia. 2011;194(1):19-23.]

Roman et al. evaluated the immunogenicity and safety of AS03A-adjuvanted influenza A (H1N1) 2009 vaccine among two age groups, 18–60 years and >60 years. Oil-in-water emulsion adjuvants are used for inactivated vaccines, e.g. AS03 from GSK, MF59 from Novartis and AF03 from Sanofi. This study was conducted in Belgium using AS03A-adjuvanted split-virion vaccine at dosage of 3.75 µg. To measure the immunogenicity, the authors used seroprotection rate, seroconversion rate and geometric mean ratio. History of seasonal flu vaccination was also evaluated from the past 3 years. On days 21 and 42 after vaccination, participants in both age groups achieved European licensure criteria. The vaccine was well tolerated and injection site pain was the most common adverse event. Although authors concluded that previous seasonal flu vaccination decreased GMT, the study power was low due to small sample size. Study quality was relatively high with Jadad score=3.

In this study, the age group of >60 years reported higher pre-vaccination antibody level compared with the other group (18–60 years). This is consistent with the findings from another paper (Booy et al., 2011) which concluded that “a pre-existing influenza A antibody reserve in most of the oldest group of people that was cross-reactive to the new pandemic (H1N1) 2009 virus; this is likely to be lifelong and to have provided them with clinical protection against the first wave of the pandemic”. In a meta-analysis of monovalent pandemic vaccine (Yin et al., 2011), similar seroprotection rates to those found by Roman et al. (2010) were reported – 93.8% in the 18–60 years age group and 87.4% in those aged >60 years.

Presented by Kevin Yin, PhD candidate, NCIRS

Effectiveness of pneumococcal polysaccharide vaccine against pneumonia and cost analysis for the elderly who receive seasonal influenza vaccine in Japan

Kawakami K, Ohkusa Y, Kuroki R, et al.
Vaccine. 2010;28(43):7063-9
Link to abstract

This study was a randomised controlled trial conducted recently in Japan. The pneumococcal polysaccharide vaccine (PPV) is not funded there for the elderly. Although its effectiveness against invasive disease is well established, many trials over many decades have provided a range of conflicting results about its effectiveness against pneumonia, which is much more common than invasive disease. They randomised 785 people aged 65 or more years who had received influenza vaccine. Half received PPV and the other half received nothing; subjects and staff were not blinded to PPV status. PPV vaccination significantly reduced the incidence of admission for all-cause pneumonia for subjects older than 75 years of age (41.5%, P=0.039) and for those who had difficulty walking (62.7%, P=0.005), but not for all study subjects older than 65 years of age (P=0.183), for the 2-year period. PPV vaccination significantly reduced medical costs for all study subjects during the first year period (P=0.027). The study demonstrated that PPV was effective for all-cause pneumonia for study subjects older than 75 years of age, although the effect was not significant for all study subjects older than 65 years of age. There have been at least two other recent studies showing some effectiveness against pneumonia, one other in Japan and one in Sweden. The evidence is mounting of some degree of possible effectiveness against pneumonia, although of a short duration.

Evidence of increasing frequency of herpes zoster management in Australian general practice since the introduction of a varicella vaccine

Nelson MR, Britt HC, Harrison CM.
Medical Journal of Australia 2010;193(2):110-3.
Link to abstract

This study examined trends over time in national GP consultations for varicella and herpes zoster (HZ). They were examining whether the introduction of the varicella vaccine had a measurable impact on GP presentations for that condition, and whether it had resulted in an increase in HZ due to reduced boosting in adults from silent infections. It used the Bettering the Evaluation and Care in Health (BEACH) cross-sectional survey, the only source of national data on primary care data for specific conditions in Australia. Regression analysis indicated a significant rise in the HZ management rate over the study period, with an average annual increase of 0.05 per 1000 encounters (P<0.01). The management rate for varicella decreased significantly from 2.01 per 1,000 encounters in 1998–1999 to 0.58 per 1,000 in 2008–2009. They concluded that the introduction of vaccination for HZ prevention at age 60 or 65 years should be considered. A letter in response to this from Associate Professor Kristine Macartney and Dr Anita Heywood from NCIRS was also discussed.* It made the point that similar increases have been seen in other settings, with and without the use of varicella vaccine. Also, their analysis of HZ hospitalisations showed an increase over time, which was no longer evident after age standardisation, indicating that the ageing population may be an important contributor to increasing rates.

* Heywood AE, Macartney KK. How can we better understand trends in varicella zoster virus-related disease epidemiology? [letter] Medical Journal of Australia 2011;194:268-9.

Presented by Dr Rob Menzies, Deputy Director – Surveillance, NCIRS

Highlights from the 9th Canadian Immunisation Conference: “Immunization: a global challenge for the 21st Century”, Quebec City, December 2010

The conference program is available at http://www.phac-aspc.gc.ca/cnic-ccni/2010/prog-eng.php

Presented by Associate Professor Kristine Macartney, Deputy Director – Government Programs, NCIRS