Journal club summaries - 2014


Impact of requiring influenza vaccination for children in licensed child care or preschool programs – Connecticut, 2012–13 influenza season

Hadler JL, Yousey-Hindes K, Kudish K, et al. 
Morbidity and Mortality Weekly Report 2014;63(9):181–5
Link to abstract

Children aged less than 5 years are at increased risk of severe influenza and hospitalisation. In the USA, influenza vaccination has been recommended since 2006 for all children aged from 6 months to less than 5 years. The Australian Immunisation Handbook currently only recommends influenza vaccination for children with underlying medical conditions, stating that it “can be used” for other children aged 6 months and over. All US states have legislation requiring that children attending licensed child care are vaccinated against certain diseases, but only Connecticut and New Jersey include influenza in the required vaccines. This study aimed to evaluate the impact of the Connecticut legislation, introduced in September 2010, on vaccination coverage and influenza-related hospitalisations in the 2012/2013 flu season. 

Vaccination coverage data were sourced from existing routine national telephone surveys (the usual way coverage is measured in the USA in the absence of a national immunisation register) and a one-off survey of child care facilities in Connecticut. Hospitalisation data were sourced from CDC’s FluSurv-NET, an active surveillance system for laboratory-confirmed influenza-related hospitalisations conducted through the Emerging Infections Programs (EIP) network. 2012/13 data were compared to 2009/10, the last season where H3N2 was the dominant circulating influenza subtype.

Main findings
Influenza vaccination coverage in children aged 6 to 59 months in Connecticut increased significantly from 67.8% (95%CI 61.1 to 74.5%) in 2009/2010 to 84.1% (95%CI 78.2 to 90.0%) in 2012/13. However, this increase was not significantly different to the 11.9% (57.9% to 69.8%) increase observed in US children over the same period. The rate of medical/religious exemption was 3 times higher for influenza vaccine (5.1%) than for other vaccines (1.7%). In 2012/13 Connecticut was one of only two out of 11 EIP sites where the influenza-related hospitalisation rate in under 5-year-olds decreased; it also had the greatest drop (12%) in hospitalisation rate and the lowest rate ratio for hospitalisations in under 5-year-olds compared to all age groups (0.53).

Take home message
This ecologic study provides some limited evidence to suggest that legislative requirements for influenza vaccination for child care attendance may increase vaccination coverage and reduce hospitalisations in the US context. This is of potential interest in the Australian context given the recent introduction of similar legislative requirements for child care attendance in NSW and Queensland, limited to National Immunisation Program (NIP) funded vaccines. If influenza vaccine eventually becomes funded under the NIP for children aged less than 5 years, inclusion in child care legislative requirements could be worth considering. 

Presented by Dr Frank Beard, Public Health Physician, NCIRS

Age-specific strategies for immunization reminders and recalls: a registry-based randomized trial

Dombkowski KJ, Costello LE, Harrington LB, et al.
American Journal of Preventive Medicine 2014;47(1):1-8
Link to abstract

Reminder and recall strategies are known to be effective in increasing immunisation rates but there is little information available on what is the optimal age to send reminder/recall notices. This study in Detroit, USA, assessed the relative effectiveness of centralised reminder/recall strategies targeting age-specific vaccination milestones: a 7-month recall strategy, a 12-month reminder strategy, and a 19-month recall strategy. Eligible children were randomised to notification (intervention) or no notification groups (control). 

Results indicated that although recall notifications can positively affect immunisation activity, the effect may vary by targeted age group. Immunisation activity was similar between notification versus no notification groups at both 7 and 12 months, suggesting that these groups were likely to receive medical care or immunisation services without prompting. Significantly more 19-month-old children in the recall group (26%) had immunisation activity following notification compared to those who did not receive a recall notification (19%). 

This study has some useful lessons for Australians. The main one is that, although reminder/recall has been frequently shown to improve coverage and timeliness, it won’t necessarily work in all situations. There are a large number of well-care visits that are recommended by state authorities in Australia which include all vaccination schedule points, but they are not always followed. The most followed visits are probably those at 6–8 weeks of age and the Healthy Kids Check at 3 years. However, the general decline in primary care contact after 1 year of age which occurs in the USA is probably also applicable in Australia. Also important is the starting point for coverage and timeliness and other infrastructure supporting immunisation, before reminders/recalls are introduced. The authors did not talk about general coverage and timeliness in Detroit before the study commenced, but the pre-existence of a system of reminders/recalls may suggest there was limited room for improvement.

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

Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China

Zhu F, Xu W, Xia J, et al.
New England Journal of Medicine 2014;370(9):818-28
Link to abstract

Enterovirus 71 (EV71) is a picornavirus which is one of several viruses which frequently cause hand, foot and mouth disease (HFM) or herpangina, a usually self-limiting childhood infection. However, in rare cases it can cause more serious infections with severe neurologic complications (including aseptic meningitis, brainstem encephalitis or acute flaccid paralysis) and can lead to permanent disability or death. Large outbreaks frequently occur across Asia, including China, where the C4 subgenotype has been predominant. This paper outlined a phase 3 trial to assess the safety and efficacy of a Vero-cell derived, inactivated EV71 vaccine developed in China.

This was a large double blind randomised controlled trial involving 10,007 children 6–35 months of age, randomised to receive an inactivated EV71 vaccine against the C4 subgenotype or placebo. Children received a 2-dose schedule, 1 month apart, and had 12 months of follow-up for laboratory confirmed EV71 infection. The authors found that the vaccine efficacy against EV71 HFM or herpangina was 94.8% and against hospitalisation and severe neurologic complications was 100%. Almost all (98.8%) participants were seropositive 28 days after the second vaccination. A titre of 1:16 was calculated as the best ‘correlate of protection’. There were no safety concerns in the vaccinated cohort compared to the placebo group. There was a drop in neutralising antibodies from the beginning through to 6 months into the observation period but levels were then stable to 12 months.

This C4 subgenotype EV71 vaccine demonstrated safety and high efficacy against EV71 HFM/herpangina, including hospitalisation and neurologic complications, with protection lasting at least 12 months. However, its cross-protection against other subgenotypes of EV71 is unknown. Multivalent vaccines may be required to be effective in more than one region of the world.

Presented by Dr Jean Li-Kim-Moy, Clinical Research Fellow, NCIRS

Safety and immunogenicity of full-dose trivalent inactivated influenza vaccine (TIV) compared with half-dose TIV administered to children 6 through 35 months of age

Halasa, NB, Gerber MA, Berry AA, et al. 
Journal of the Pediatric Infectious Diseases Society Advance Access published 27 June 2014
Link to abstract

Currently in the USA, where this study was undertaken (and in Australia), the recommended dose of trivalent inactivated influenza vaccine (TIV) for children between 6 and 35 months of age is the half-dose (7.5mcg haemagglutinin antigen (HA) in 0.25mL). However, this recommendation was based on trials of a whole-virus influenza vaccine in the 1970s in which a full dose (15mcg HA in 0.5mL) caused an increase in adverse events in children compared to adults. Halving the dose for children under 36 months of age decreased the severity and rates of adverse events to an acceptable level. The authors questioned whether using a half-dose is still necessary with the current use of less reactogenic split-virus TIVs. 

The aim of this study was to compare the safety profile and immunogenicity of a full-dose versus a half-dose of TIV in children aged between 6 and 35 months. It was conducted across two influenza seasons (October 2010 to March 2012) and included 243 children in two cohorts: a ‘primed’ cohort (who had received 2 doses of 2009–2010 H1N1 influenza vaccine and 2 doses of any TIV in the past) and a naïve cohort. The primed cohort received 1 dose of either 0.25mL or 0.5mL TIV and the naïve cohort received 2 doses of either 0.25mL or 0.5mL of the same vaccine (Fluzone, Sanofi Pasteur). Local and systemic adverse events were recorded by parents for 7 days after vaccination and antibody levels were measured prior to vaccination and 1 month after the last dose of vaccine.

There were no significant differences in local or systemic reactions, regardless of dose, and few significant differences in immunogenicity to the three vaccine antigens. The immune response to H1N1 was significantly higher in the full-dose group among those children who were primed. In the naïve cohort, the geometric mean titres for all three antigens after 3 doses of TIV were significantly higher in children aged 12–35 months than in children aged 6–11 months. 

The study had several limitations. The trial was conducted over two influenza seasons meaning that some children may have developed influenza disease that was not medically attended – this could have affected the immunogenicity data. Also, the study was originally powered for safety only and so may not have had sufficient subject numbers for detection of significant differences in immunogenicity. 

The authors sited several other studies that found similar results, in particular a Finnish study which reported effectiveness of a 0.5mL dose in children of all ages from 6 months. The full-dose is now recommended for all children from 6 months of age in Finland, the UK and Canada based on the data from the Finnish study.

Presented by Kath Cannings, Immunisation CNC, NCIRS

Understanding vaccine hesitancy around vaccines and vaccination from a global perspective: a systematic review of published literature, 2007-2012

Larson HJ, Jarrett C, Eckersberger E, et al. 
Vaccine 2014;32(19):2150-9
Link to abstract

The Vaccine Confidence Index group, led by Heidi Larson, conducted a systematic review of the literature on vaccine hesitancy. The review was conducted for the Strategic Advisory Group of Experts Working Group (SAGE WG), and originally presented on their website in 2013. The SAGE WG had a prior model of hesitancy, the development of which will be informed by the results of this review. The authors identified a variety of factors associated with vaccine hesitancy but the independent and relative strength of influence of each factor is complex and context-specific, varying according to time, place and vaccine. Some determinants may be associated with both increased and decreased vaccine hesitancy. The authors noted an increasing rate of publications on vaccine hesitancy, and showed that low-income countries, despite having higher populations, are under-represented in this area of research.

Presented by Dr Hal Willaby, Research Fellow, NCIRS

Protective association between rotavirus vaccination and childhood seizures in the year following vaccination in US children

Payne DC, Baggs J, Zerr DM, et al.
Clinical Infectious Diseases 2014;58(2):173-7
Link to abstract

Illness due to rotavirus infection has been linked to childhood seizures, severe gastroenteritis and antigenaemia. Rotavirus has also been isolated in cell culture from the sera of infected children, confirming the existence of viremia and the potential for systemic illness. Since rotavirus vaccine has resulted in substantial declines in severe gastroenteritis among US children, the authors investigated whether receipt of rotavirus vaccine protects children from being hospitalised or visiting the emergency department for seizures in the year after vaccination.

Data was analysed retrospectively for a cohort of children born between March 2006 and November 2009. The rate of seizures in fully vaccinated and unvaccinated children, from 4 to 55 weeks following last rotavirus vaccination, were compared. 

Of the 250,601 infants in the cohort, 186,502 children (74%) were fully vaccinated and 64,099 (26%) were not vaccinated with rotavirus vaccine. Rates of seizures were found to be associated with rotavirus vaccination status. A full course of rotavirus vaccination was associated with an 18–21% reduction in the risk of seizure. The protective effect of a full course of rotavirus vaccination applied to both first-ever seizures and all seizures.

The authors equated these results to the prevention of about 1000 hospitalisations and 5000 emergency department visits for seizures per year in young children and a reduction in health care costs of over $7 million. This is in addition to the well-documented vaccine-related benefit of preventing hospitalisations due to diarrhoea. 

Presented by Dr Deepika Mahajan, Senior Research Officer, NCIRS

Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial

Pollard RB, Rockstroh JK, Pantaleo G, et al. 
The Lancet Infectious Diseases 2014;14(4):291-300
Link to abstract

There is no prophylactic or therapeutic HIV vaccine available yet. This is due to the failure, but not a lack, of effects. Obstacles to HIV vaccine development include: (1) HIV integration into host cell chromosomes; (2) high HIV variability; (3) lack of a correlate of protection; and (4) lack of strong (and broadly) neutralising antibodies. Many candidates for prophylactic HIV vaccines have been evaluated. Several publications repeatedly demonstrated that one candidate for a T cell-based vaccine (vector: adenovirus type 5) did not reduce the risk of acquiring HIV infection. 

Pollard and colleagues’ study tested a peptide-based therapeutic vaccine targeting HIV-1 p24Gag (Vacc-4x). This was a multi-centre, randomised controlled trial; random assignment was 2:1 for Vacc-4x (4 primary doses plus 2 boosters) or placebo. A total of 174 HIV infected individuals were recruited.

The study showed no significant difference between vaccinees and controls in: (1) the percentage resuming combination antiretroviral therapy (cART) after cART interruption; (2) the mean number of days before returning to cART; and (3) the percentage change in CD4 count. However, the authors reported a significant reduction of viral load among vaccinees at both week 48 and week 52 of the study.

The vaccine was generally safe and well tolerated. Most adverse events were local reactions. One vaccinee experienced exacerbation of multiple sclerosis, reported as possibly related to study treatment. One death occurred among controls (due to myocardial infarction). 

In summary, the Vacc-4x (HIV-1 p24Gag conserved peptide) therapeutic vaccine given during cART interruption had a good safety profile and reduced viral load, but it had no effect on cART resumption or changes in CD4 count over time.

Presented by Dr J Kevin Yin, Research Officer, NCIRS

A phase I clinical study of a live attenuated Bordetella pertussis vaccine – BPZE1; a single centre, double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally to healthy adult male volunteers

Thorstensson R, Trollfors B, Al-Tawil N, et al.
PLOS One 2014:9(1):e83449
Link to text 

Pertussis is poorly controlled in Australia, and many other countries, despite high levels of vaccination coverage. A key contributing factor is that immunity from acellular pertussis vaccines wanes quickly. It is now generally acknowledged that satisfactory control is unlikely to be achieved until a more effective vaccine is developed. As natural infection induces a strong immune response, live attenuated pertussis vaccines could be the answer. 

This paper reports on a phase 1 clinical trial assessing safety and immunogenicity of a genetically modifiedBordetella pertussis strain (BPZE1), a live attenuated nasal pertussis vaccine developed by genetically eliminating or detoxifying three key toxins. It was a placebo-controlled double-blind dose-escalation trial in healthy adult male volunteers aged 19–31 years, born in Sweden between 1979 and 1991 when no pertussis vaccine was in use. Exclusion criteria included clinical pertussis (laboratory verified) in the previous 10 years or a serum anti-pertussis toxin IgG of 20 IU/mL or higher. 

There were 16 individuals in each of three dose groups (low, medium and high dose), with 12 in each group given BPZE1 and 4 given diluent only. Each group was followed for around 2 months before the next group was vaccinated. Nasopharyngeal aspirates were collected and cultured to determine colonisation by BPZE1 at 4, 7, 11, 14, 28 (and, if necessary, 45) days after vaccination. Blood was also collected for antibody testing. 

Only one person was lost to follow-up, due to the only serious adverse event (death at 7 weeks, judged to not be vaccine related). There was no difference in adverse events between the placebo and treatment groups, or between colonised and non-colonised subjects. 

BPZE1 was isolated between days 4 and 14 in one person in the low-dose group, one person in the medium-dose group, and five in the high-dose group. At 28 days, only one person was still colonised, who was culture negative at 49 days. Colonisation was significantly more common in the high-dose group than in the low/medium-dose groups combined. A pronounced difference in antibody response was seen between colonised and non-colonised subjects. Non-responders in the high-dose group had significantly higher pre-vaccination antibody levels than responders, which may indicate previous subclinical infection. 

Future studies to explore whether pre-existing immunity prevents BPZE1 colonisation, and whether higher doses can overcome this, are required. 

Presented by Dr Frank Beard, Staff Specialist – Public Health Physician, NCIRS

Global control and regional elimination of measles, 2000–2012

Perry RT, Gacic-Dobo M, Dabbagh A, et al.
Morbidity and Mortality Weekly Report 2014;63(05):103-7
Link to text

This report describes progress toward global control and regional elimination of measles during 2000–2012. The annual reported measles incidence was 33 reported cases per million population in 2012, a decline of 77% from 146 cases per million population in 2000. Increases in routine measles-containing vaccine (MCV) coverage, plus supplementary immunisation activities, reached 145 million children in 2012. The estimated global coverage for the first dose of MCV was 84% in 2012 and the number of countries providing a second dose of MCV increased from 96 (50%) in 2000 to 145 (75%) in 2012. 

Despite the increase in coverage, outbreaks of measles during 2012 were reported in the Democratic Republic of the Congo (72,029 cases), India (18,668), Indonesia (15,489), Ukraine (12,746), Somalia (9,983), Sudan (8,523), Pakistan (8,046) and Romania (7,450). China reported 6,183 cases, an historic low after a steady annual decrease from 38,159 cases in 2010. Genotyping results from isolates from persons with measles were reported from 49 (39%) of the 125 member states reporting measles cases in 2012; six measles genotypes were identified. 

All regions had substantial reductions in estimated measles mortality, ranging from 52% in the Eastern Mediterranean Region to 88% in the African Region. Compared with a scenario of no vaccination, an estimated 13.8 million deaths were prevented by measles vaccination during 2000–2012 and estimated measles deaths decreased 78%, from 562,400 to 122,000. 

By 2012, regional verification commissions were established in the Region of the Americas, the European Region and the Western Pacific Region, and frameworks for documenting elimination were developed in the Americas and Europe. To accelerate progress toward reaching elimination targets, national governments would need to give these efforts high priority, increase the visibility of measles elimination activities and provide adequate resources.

Limitations of this study include inaccuracies in MCV coverage estimates based on inaccurate estimates of the size of the target population, inaccurate reporting of doses delivered, and inclusion of doses given to children outside the target age group during supplementary immunisation activities. Furthermore, there could be underestimation in surveillance data as not all patients with measles seek care and not all of those who seek care are reported. Additionally, in some countries, there could be multiple reporting systems for measles and inclusion of aggregate, unconfirmed cases rather than case-based data.

Presented by Dr Aditi Dey, Manager Surveillance, NCIRS