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Journal Club summaries - 2010

Pertussis disease burden in the household: how to protect young infants

de Greeff SC, Mooi FR, Westerhof A, et al.
Clinical Infectious Diseases 2010;50(10):1339-45
Link to abstract

A strength of this study is the high number of identified household contacts who underwent laboratory diagnostic testing for pertussis (723 of 738, 98%), a figure much higher than many previous studies.

The results of this study are in agreement with many of the recently published pertussis source of infection studies which identify the mother as a prominent source of infection of infant pertussis cases. A point of difference of this study is the identification of siblings as being the most likely source of infection in this case. This finding concurs with a small number of Australian source of infection studies, including study populations of both hospitalised and non-hospitalised infant pertussis cases, which also found siblings to be a likely source of infection. 

When considering the generalisability of these results, one should be mindful that the Dutch immunisation schedule was changed from a whole-cell vaccine (Dutch DTP-IPV-Hib) to an acellular vaccine in 2005 (Infanrix-IPV-Hib [GSK-Belgium] and later Pediacel [Sanofi PasteurMSD-Canada]). The results of this study demonstrated that children vaccinated with the whole cell vaccine were more likely to acquire pertussis infection than those vaccinated with the acellular vaccine, which may explain the higher prominence of siblings as a source of infection in this study.

These results support the rationale behind a "cocooning" strategy – the immunisation of household contacts of newborn infants – to protect this vulnerable group against pertussis.

Presented by Kerrie Wiley, Research Assistant, NCIRS

A decline in varicella but an uncertain impact on zoster following varicella vaccination in Victoria, Australia

Carville KS, Riddell MA, Kelly HA
Vaccine 2010;28(13):2532-2538 
Link to abstract

In Australia, the varicella vaccine (VV) has been available on the private market since 2000 and was placed on the National Immunisation Program (NIP) in November 2005 for infants aged 18 months with a school-based catch-up campaign for 12–13 year olds. The aim of this study was to evaluate the impact of this program on hospitalisations and calls to the Melbourne Medical Deputising Service (MMDS) for VZV disease – both primary varicella and herpes zoster. This study reports on the yearly trends in varicella and zoster-related hospitalisations in Victoria, Australia, and compares hospitalisation rates and patient characteristics across three periods of vaccine availability. 

This study shows that the hospitalisation rates for any diagnosis of varicella and for a principal diagnosis of varicella declined after placement of VV on the NIP, with principal varicella hospitalisations declining from 4.0 per 100,000 (95% CI: 3.8–4.2) in the period prior to vaccine availability and 4.2 per 100,000 (95% CI: 4.0–4.4) during availability on the private market to 3.1 per 100,000 (95% CI: 2.6–3.7) in the 2 years since funding on the NIP. The decline has been predominately seen in children under 5 years of age with the decline emulated in the MMDS data. After NIP listing, a decline in hospitalisations was also seen in adults aged 20–49 years, with a 39% decline between private and public vaccine periods. This decline has resulted in a significant increase in the median age of hospitalisations containing coding for varicella. 

This study also shows that the hospitalisation rates for a principal diagnosis of zoster have increased an average of 5% per year (95% CI: 3%–6%) between 1998 and 2007 with a significant increase between private and public VV availability in hospitalisations among those aged 80 and over. However, these results are limited by the ecological nature of the study and that multiple admissions for the same individual are likely in the elderly and may be increasing with an ageing population. This may also be reflected in the significant increase in median age in zoster hospitalisations from 71 years (IQR 54–81) prior to vaccine availability, to 73 years (IQR 58–81) during VV private availability to 76 years (IQR 61–83) during the VV NIP program period. 

Presented by Anita Heywood, Research Assistant, NCIRS

Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management

Mantadakis E, Farmaki E, Buchanan GR
Journal of Pediatrics 2010;156(4):623-8
Link to abstract

Immune thrombocytopenia purpura (ITP) is an autoimmune disorder with bleeding tendency. The measles-mumps-rubella (MMR) vaccine was reported to be likely associated with benign thrombocytopenia purpura (Demicheli et al., 2005). However, there was no systematic review looking at the causal relationship between ITP and MMR vaccine. Mantadakis and colleagues did a systematic review based on 12 studies and assessed the incidence of ITP after MMR vaccination compared with natural measles and rubella, and the clinical course, outcome and recurrence. They concluded that MMR-associated ITP is rare and benign. The findings of this systematic review are valuable for clinical practice and policy making around MMR vaccination. 
Demicheli V, Jefferson T, Rivetti A, Price D. Vaccines for measles, mumps and rubella in children. Cochrane Database of Systematic Reviews 2005;(4):CD004407

Presented by Dr Kevin Yin, Research Assistant, NCIRS

Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial

Zhu FC, Zhang J, Zhang XF, et al.
Lancet 2010;376(9744):895-902 
Link to abstract

This study was a phase 3 randomised double-blind controlled clinical trial on the Chinese HEV 239 recombinant hepatitis E vaccine among healthy adults aged 16–65 years in the Jiangsu province of China, where hepatitis E is endemic and both genotypes 1 and 4 co-circulate, with the zoonotic genotype 4 being the dominant genotype. More than 120,000 participants from 11 townships were enrolled. The study vaccine was a recombinant vaccine based on the bacteria E. coli and derived from genotype 1 of the hepatitis E virus adjuvanted with aluminium hydroxide. The control vaccine was a recombinant hepatitis B vaccine adjuvanted with aluminium hydroxide. The schedule was a 3-dose primary course administered at 0, 1 and 6 months. 

Seropositivity was detected in 47.8% and 46.9% of a subgroup of participants (from two townships) among the study and the control groups, respectively, prior to vaccine administration. The vaccine efficacy of HEV239 of the per-protocol population (those who received all three doses at the appropriate times) in this study was 100% (95% CI 72.1–100.0%) during the 12 months from the 31st day after the receipt of the third dose (months 7–19 post first dose), the primary outcome measure. The efficacy estimates were also 100% for subgroups of males, females, those aged 16–49 years and those aged 50–65 years, although the confidence intervals were wider, with some efficacy estimates being statistically not significant. For those who received at least one dose of the vaccine, the vaccine efficacy estimate was 93.8% (95% CI 59.8–99.9%) during months 7–19 post first dose. There was no separate reporting of analyses among subjects who were seronegative prior to vaccination. The great majority (12/13, 92%) of hepatitis E cases that were genotyped were of genotype 4, and the remaining 1 was a genotype 1 virus, suggesting that this genotype-1 derived vaccine provided cross-protection against genotype 4 disease. Seroconversion was detected in 98.7% (5,494/5,567) of subjects receiving the study vaccine and in 2.1% (119/5,598) of subjects receiving the control vaccine at 1 month after the final (third) vaccine dose.
The duration of the vaccine-induced immunity is unknown. 

Further studies to inform possible population vaccination policies using hepatitis E vaccines, such as in a younger population with low seroprevalence or women of child-bearing age, would be valuable. There is also a need to study the use of this vaccine in population groups who are at high risk of mortality and poor outcome from hepatitis E, including patients with chronic medical conditions (in particular those with chronic liver disease), children (especially young children and infants), and pregnant women.

Presented by Dr Clayton Chiu, Public Health Physician, NCIRS

Breastfeeding and risk for fever after immunization

Pisacane A, Continisio P, Palma O, et al.
Pediatrics 2010;125(6):e1448-52
Link to abstract

The aim of this study was to investigate the incidence of fever following immunisations among breastfed and non-breastfed infants who attended the vaccination centre of district 49 of Naples, Italy, between 2008 and 2009.

The participants were infants scheduled to receive their 1st or 2nd dose of hexavalent combination vaccine, co-administered with heptavalent pneumococcal conjugate vaccine. The Italian immunisation program schedules these vaccinations at 3 months and 5 months, respectively. 450 infants were enrolled in the study.

A significant difference was reported in the adjusted relative risk for fever between the breastfed and non-breastfed groups, with breastfeeding found to have a protective effect against the outcome of fever following immunisation.

Presented by Ms Kerrie Wiley, Research Assistant – Policy Support, NCIRS

Phase I/II, open-label trial of safety and immunogenicity of meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine in human immunodeficiency virus-infected adolescents

Siberry GK, Williams PL, Lujan-Zilbermann J, et al.
Pediatric Infectious Disease Journal 2010;29(5):391-6
Link to abstract

This is a well documented study. However, it is limited to data from the first month of study results, i.e. safety and immunogenicity data following first dose of MenactraTM.

Results: The vaccine is safe and immunogenic but the study found decreasing antibody responses with increasing immunosuppression/disease progression as one might expect in an HIV-infected population.

The study is powered (80%) to detect an odds ratio of 2.5 between the week 72 immunogenic response (GTE 4-fold increase in rSBA titre) for the group that receives 1 dose (at day 0) vs the group that receives 2 doses (day 0, week 24); 2-sided p = 0.05, given serogroup C response = 70% in the 1-dose group. At 4 weeks post dose 1, 52% of subjects had a GTE 4-fold increase in serogroup C rSBA.

Further reports should be expected from this study.

Presented by Dr Leon Heron, Medical Manager - Vaccine Trials, NCIRS

Parental vaccine safety concerns in 2009

Freed GL, Clark SJ, Butchart AT, et al.
Pediatrics 2010;125(4):654-9
Link to abstract

This paper presents results of an online survey of 2,521 parents of children aged Of the 2,521 surveys fielded, 1,552 parents responded to the survey. Most parents agreed with the statement that vaccines are a good way to protect their children from diseases and that they generally agree with what their doctor recommends regarding vaccines. However, around 54% of parents expressed concerns regarding serious adverse effects of vaccines. 
Hispanic parents were more likely (37%) than white (22%) or black (23%) parents to believe that vaccines cause autism in healthy children. However, black parents were more likely (15%) than white (12%) or Hispanic (5%) parents to have ever refused a vaccine recommended by their doctor. HPV was the most commonly refused vaccine.

Overall, significant numbers of parents are vaccinating their children. Although information is available to address many vaccine safety concerns, such information is not reaching parents in an effective manner. 

Therefore, Public Health Officials need to construct and redesign vaccine information programs to address these safety concerns.

Presented by Swati Ghotane, Research Assistant, NCIRS

Influenza vaccination among healthcare workers: ten-year experience of a large healthcare organization

Ajenjo MC, Woeltje KF, Babcock HM, et al.
Infection Control and Hospital Epidemiology 2010;31(3):233-40
Link to abstract

Mandatory influenza vaccination in health care workers (HCW) has been a controversial topic for a long time in Australia and internationally. This study described the results of different measures implemented to improve adherence to HCW influenza immunisation programs at 11 hospitals in mid-Western USA from 1997 to 2007. Data analysis consisted of two components: 1) review and analysis of data from the occupational health departments of the hospitals; and 2) interviews with key stakeholders involved in carrying out the interventions. Influenza vaccination coverage rates increased from 45% to 72% from 1997 to 2007 (p<0.001). Five hospitals had rates that exceeded the target goal of 80% in 2007. The most successful interventions were adding influenza vaccination rates to the "quality scorecard incentive program" and the use of "declination statements". The most important barriers to success identified by interviewees were HCW's misconceptions about influenza vaccination and a perceived lack of leadership support. The study suggested more aggressive interventions such as implementing mandatory influenza vaccination policies to achieve higher vaccination rates. Findings of this study were also compared with those from an evaluation study of the NSW Health policy "Occupational assessment, screening and vaccination against specified infectious diseases". Lessons for Australia included the importance of "involving leadership level staff in the interventions", "the need for having a consistent and universal database for recording vaccination status across hospitals", and "the need to address HCW's misconceptions of influenza vaccination".

Presented by Maria Chow, Research Assistant, NCIRS

Association between the 2008–09 seasonal influenza vaccine and pandemic H1N1 illness during spring–summer 2009: four observational studies from Canada

Skowronski DM, De Serres G, Crowcroft NS, et al. 
PLoS Medicine 2010;7(4):e1000258. doi:10.1371/journal.pmed.1000258
Link to abstract

In late spring 2009, concern was raised in Canada that prior vaccination with the 2008–09 trivalent inactivated influenza vaccine (TIV) was associated with increased risk of pandemic influenza A (H1N1) (pH1N1) illness. Several epidemiologic investigations were conducted through the summer to assess this putative association.

Studies included: (1) test-negative case-control design based on Canada's sentinel vaccine effectiveness monitoring system in British Columbia, Alberta, Ontario, and Quebec; (2) conventional case-control design using population controls in Quebec; (3) test-negative case-control design in Ontario; and (4) prospective household transmission (cohort) study in Quebec. 

The authors concluded that "Prior receipt of 2008–09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring–summer 2009 in Canada." Possible biological mechanisms and immunoepidemiologic implications are considered.

The authors have gone to considerable lengths to limit possible bias through adjustment in the analysis and using different methods in four different studies. However, they state that "The occurrence of bias (selection, information) or confounding cannot be ruled out." 

Six previous studies, also observational, have found either no association between TIV and pH1N1 infection, or a protective effect. This is a good illustration of the difficulties in interpreting observational studies given the possibility of undetected bias. The jury is still out on this issue.

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

The early kinetics of circulating pneumococcal-specific memory B cells following pneumococcal conjugate and plain polysaccharide vaccines in the elderly

Baxendale HE, Keating SM, Johnson M, et al.
Vaccine 2010;28(30):4763-70
Link to abstract

Two types of pneumococcal vaccines have been developed, both premised on the use of the pneumococcal serotype-specific capsular polysaccharides: the pneumococcal conjugate vaccines (PCV) contain polysaccharides that are coupled to a carrier protein, whereas the plain polysaccharide vaccines (PPV) do not 
utilise a carrier protein. In Australia the PCV PrevenarTM is indicated for use in infants and children, whereas the PPV PneumovaxTM is recommended for adults aged >/=65 years (>/=50 years in Aboriginal and Torres Strait Islander people). However, PneumovaxTM induces a short-term immune response in the elderly, which is believed to be due to the fact that polysaccharides are T-independent antigens which induce a weak and shorter antibody response and no immune memory. On the other hand, PCVs have been shown to be highly immunogenic in young children and can prime long-lived memory cells. Recently the potential of using PCVs for increased protection again invasive pneumococcal disease (IPD) in the elderly is being considered; however, the results conflicting.

This paper aims to compare whether immunisation with the PCV PrevenarTM compared with PPV PneumovaxTMresults in enhanced recruitment of PPS-specific plasma and memory B cells to the circulation in an elderly cohort up to 1 month after immunisation, to assess the feasibility of their use in the elderly population. The study recruited 37 adult participants (52–74 years of age) who were randomly allocated to receive either PrevenarTM or PneumovaxTM. Blood samples were taken on days 0, 7 and 28 and used to determine the serotype-specific serum antibody response (IgA, IgM and IgG) as well as isolation and quantification of polysaccharide-specific antibody secreting plasma or memory B cells. Following vaccination, there was a statistically significant increase in IgG, IgA and IgM concentrations for most vaccine serotypes at day 7 and a further increase at day 28. There was no significant difference in serotype-specific IgG, IgA or IgM concentration between the two vaccine groups at each bleed point. In addition, as determined by ELISPOT, the authors reported no difference between the kinetics of the early PBMC-derived B cell response following immunisation between the two groups and concluded that pneumococcal conjugate vaccines may not quantitatively enhance the generation of memory response in the elderly.

These include the small number of study participants; the limited number of PPV samples that were available for analysis at the day 28 bleed; the feasibility of using PBMC-derived B cells to establish antigen-specific memory response in the elderly; and that functionality of vaccine-induced antibodies was not assessed. The authors suggested larger and longer studies of this type in the elderly to provide further evidence on the use of PCV in this population. 

Presented by Dr Melina Georgousakis, Research Officer, NCIRS

Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures

Klein NP, Fireman B, Yih WK, et al.
Pediatrics 2010;126(1):e1-e8
Link to abstract

In 2008, the Advisory Committee on Immunization Practices (ACIP) in the USA were informed of preliminary findings by the Centers for Disease Control (CDC) Vaccine Safety Datalink (VSD) that measles-mumps-rubella-varicella (MMRV) vaccine was associated with an increased risk of febrile seizures compared to concomitant vaccination with MMR and varicella vaccine (VV). Klein et al. provide updated results of this analysis. The primary outcome was the relative risk of febrile seizures resulting in emergency department (ED) visit or hospitalisation in children aged 12–23 months 0–42 days after receipt of their first dose of MMRV vaccine compared to a largely historical comparison group who received a first dose MMR + VV vaccine. The results were adjusted for age, VSD site, calendar year and respiratory virus season. Supplementary analysis included temporal scan statistics to determine the high risk period, assessment of outpatient fever visits, a chart review of seizure ED and hospitalisation visits and sub-analyses based on the results of the chart review. 

The risk of a febrile seizure peaked at 7–10 days post vaccination for all measles-containing vaccines. There was no temporal clustering after receipt of VV alone. Post-vaccination fever outpatient visits also peaked at 7–10 days post vaccination. The adjusted relative risk of a seizure 7–10 days post vaccination with MMRV compared to MMR + VV was 1.98 (95% CI 1.43–2.73) with an excess risk of 4.6 (95% CI 2.8–5.9) seizures per 10,000 doses of MMRV administered or 1 additional seizure for every 2,300 doses of MMRV administered. These findings are consistent with previous studies of febrile seizure risk after MMR vaccine, clinical trial data showing an increased fever risk after receipt of MMRV vaccine and the preliminary results reported to the ACIP. This study confirms that the use of MMRV as a first dose of measles-containing vaccine in children aged 12–23 months approximately doubles the risk of fever and febrile seizures compared to concomitant receipt of MMR + VV vaccines. 

Presented by Dr Anita Heywood, Research Officer, NCIRS

Pentavalent rotavirus vaccine and prevention of gastroenteritis hospitalizations in Australia

Field EJ, Vally H, Grimwood K, Lambert SB
Pediatrics 2010;126(3):e506-e512
Link to abstract 

Rotavirus is the leading cause of severe acute gastroenteritis (AGE) in early childhood. A publicly funded, universal infant pentavalent rotavirus vaccine (RV5) program was implemented in Queensland on 1 July 2007. The study determined the vaccine effectiveness (VE) of three doses of RV5 for preventing acute rotavirus and non-rotavirus gastroenteritis (AGE) hospitalisation in the first annual birth cohort of eligible children and explored the impact on hospitalisations in all other age groups. Furthermore, the study compared hospitalisation rates before and after RV5 introduction for rotavirus and non-rotavirus AGE in all age groups. Data was collected from routinely collected, publicly funded state-based and national data sets for vaccine coverage, hospitalisation and vaccination status. In addition, data linkage was performed to calculate three-dose VE for preventing hospitalisation in the eligible age group. The study found very high three-dose VE (89.3%–93.9% for any/primary diagnosis) for preventing rotavirus hospitalisation and 62.2%–63.9% (for any/primary diagnosis) VE for preventing non-rotavirus AGE hospitalisation. There were reductions in rates of rotavirus hospitalisation in those younger than 20 years and non-rotavirus AGE hospitalisation in those younger than 5 years. This study provided ecological evidence of reductions in hospitalisation rates in older, unvaccinated children and adolescents (rotavirus and non-rotavirus AGE) and recommended that additional post-implementation research was required to identify means to improve three-dose vaccine coverage and to understand better the effectiveness variations in other settings. 

Presented by Dr Aditi Dey, Epidemiologist, NCIRS

Prioritizing healthcare worker vaccinations on the basis of social network analysis

Polgreen PM, Tassier TL, Pemmaraju SV, Segre AM
Infection Control and Hospital Epidemiology 2010;31(9):893-900
Link to abstract

Background: Nosocomial influenza can bring devastating outcomes for patients, and outbreaks in healthcare settings can cause serious staff shortages. Influenza vaccination rates for healthcare workers (HCW) have been consistently low. Applying the social network theory helps design more effective vaccination strategies. 
Methods: Human contacts of 148 HCW across 15 job categories were observed between January and December 2006 in a large healthcare facility in the USA. Contact graphs were constructed to represent the social network of the hospital and to model the spread of influenza. The observation data were used in a model to compare a targeted vaccination strategy with other vaccination strategies. 
Results: 6,654 contacts were recorded in 606 hours. Unit clerks, X-ray technicians, social workers, transporters, and physical and occupational therapists had the most contacts. Preferentially vaccinating healthcare workers in more connected job categories resulted in a substantially lower attack rate and fewer infections than a random vaccination strategy, accounting for all simulation parameters.
Discussion: Social network models can be used to derive more effective vaccination policies, which are particularly crucial during vaccine shortages or in facilities with low vaccination rates. This can be applied to other healthcare associated infections for more effective interventions. It would be worthwhile to compare and contrast the cost-effectiveness of implementing this strategy versus mandatory influenza vaccination.

Presented by Maria Chow, Research Assistant, NCIRS