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Journal Club summaries - 2009

Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine

Slade BA, Leidel L, Vellozzi C, et al.
JAMA 2009;302(7):750-7
Link to abstract

Marketing HPV vaccine: implications for adolescent health and medical professionalism

Rothman SM, Rothman DJ
JAMA 2009;302(7):781-6
Link to abstract

Slade et al paper: This paper presents VAERS data following over 23 million doses of HPV vaccine having been distributed in the US. The most common reported adverse events were syncope, local reactions, dizziness, nause and headache. Few serious adverse events were identified, including venous thromboembolic events, most of which were in individuals who had another co-existing risk factor, and these are currently being evaluated further. This data provides reassurance as 94% of reports were minor and self-limiting and very relevant for Australian audiences, particularly when clinicians are faced with a patient reporting an adverse event and wondering if this has occurred before. It needs to be emphasised that a report of an adverse event following vaccination, especially months after the vaccine, as in some cases of clots and deaths reported, does not imply causality.

Rothman et al paper: This paper reports on the marketing of HPV vaccine and the manufacturer's decision to promote it first and foremost as a means to prevent cervical cancer, rather than HPV infection. It also reports on the use of professional medical associations as "tools" in the marketing. It reviews the educational materials developed by these associations along with pharmaceutical companies and suggest that they were biased and designed to maximise sales and as advocacy tools. It is an interesting paper, worth a read, but does omit some details, including information on how the associations were funded. The advertising and promotional environment in the US is very different to Australia.

The combination of this paper with the VAERS report and accompanying editorial in the one edition of JAMA is designed to capture readers' attention.

Presented by Dr Nick Wood, Clinical Research Fellow, NCIRS

Kinetics of pertussis immune response to tetanus-diphtheria-acellular pertussis vaccine in health care personnel: implications for outbreak control

Kirkland KB, Talbot EA, Decker MD, Edwards KM
Clinical Infectious Diseases 2009;49(4):584-7
Link to abstract

Editorial commentary: Bordetella pertussis booster vaccination for health care personnel immediately following a pertussis outbreak in a hospital?

Birkebaek NH
Clinical Infectious Diseases 2009;49(4):588-90

Pertussis outbreaks among health care personnel pose substantial risk to patients, especially infants. In adults, prevention through vaccination of health care personnel remains an attractive option. Also, vaccination of health care personnel particularly protects vulnerable infants and elderly from the risk of nosocomial pertussis. The aim of this brief report was to assess the kinetics of humoral immune response to pertussis antigens following vaccination of health care personnel (physicians, staff and volunteers) with adult tetanus-diphtheria-acellular pertussis vaccine (dTpa). One hundred and fifteen asymptomatic participants were recruited with median age of 45 years (range 19–79 years) and serum samples were collected before vaccination and at 1, 2 and 4 weeks post vaccination. All participants were asked if they experienced any respiratory illness during or after the study. Approximately 50% of the subjects demonstrated antibody response to all pertussis antigens at 1 week post-vaccination, >87% demonstrated antibody response to all pertussis antigens at 2 weeks post vaccination. Antibody responses at 2 and 4 weeks were nearly the same for all antigens. Results suggest early dTpa may be valuable to prevent illness and transmission among adults in pertussis outbreak settings. 

Editorial commentary: Discussed brief limitations of the brief report. Firstly, the small sample size and lack of non-vaccinated comparative control group thereby decreasing the impact of the study. Secondly, confirmation of cases by PCR or culture would be worth consideration in future studies. 

Presented by Mamta Porwal, Research Officer, NCIRS 

Invasive Haemophilus influenzae infections in Germany: impact of non-type b serotypes in the post-vaccine era

Kalies H, Siedler A, Grondahl B, et al.
BMC Infectious Diseases 2009;9:45
Link to article 

This paper describes the epidemiology of invasive Haemophilus influenzae (Hi) disease caused by both capsulated and non-capsulated strains in children under 10 years of age during 8 years (1998–2005) of active surveillance in the post Haemophilus influenzae b (Hib) conjugate vaccine era in Germany. The study aims in particular to assess a potential shift towards more capsulated non-b and non-capsulated Hi (grouped together as non-type b Hi strains) invasive infections in a backdrop of high Hib vaccine coverage. A similar study among Canadian children reported an increase in the annual average incidence of invasive disease due to non-type b Hi strains during a 6-year period (1996–2001) in the era of universal vaccination against Hib. The proportion of cases of invasive Hi disease caused by non-type b strains was 51% in this study compared to 60% in the Canadian study. The serotype causing the highest proportion of capsulated non-type b Hi infections was ‘f’ among German children, whereas it was serotype ‘a’ in Canadian children. Seven out of 64 Hib cases reported in this study had received a complete course of either PRP-OMP or PRP-T conjugate Hib vaccine prior to disease onset. Morbidity and mortality due to invasive non-type b Hi infections was greater than invasive Hib infections. Detailed information on the epidemiology of non-type b invasive Hi disease in Australia in the post Hib vaccination era is not available for comparison. Together with Hib carriage rates it would be useful to monitor the patterns of non-type b invasive Hi disease occurrence to understand the full impact of Hib conjugate vaccines. 

Additional reading 
McConnell A, Tan B, Scheifele D, et al. Invasive infections caused by Haemophilus influenzae serotypes in twelve Canadian IMPACT centres, 1996–2001. Pediatric Infectious Disease Journal 2007;26:1025-31

Presented by Dr Sanjay Jayasinghe, Senior Policy Officer, NCIRS 

Socioeconomic impact of influenza on healthy children and their families

Principi N, Esposito S, Marchisio P, et al.
Pediatric Infectious Diseases Journal 2003;22(10 Suppl):S207-10
Link to abstract 

The findings of this Italian study are very relevant to Australia at this point of time, especially considering the impact of swine flu among young children. While scientists and the community are extremely concerned about the clinical implications of swine flu, researchers should also bear in mind that children and their household contacts can be affected severely in terms of quality of life, and lost school or work days. This study demonstrated that children with influenza tend to have longer durations of fever and absenteeism from day care or school when compared with those without influenza (p<0.0001). The household contacts of children with influenza also had more medical visits, missed work or school days, and the need for help at home to take care of sick children (p<0.0001). Having seen the significant socioeconomic impact brought by influenza to families, the authors emphasised the need to introduce programs to vaccinate children in order to protect the children themselves, as well as their household contacts. They also suggested that economic modelling of influenza immunisation programs should be done. 

Presented by Maria Chow, Research Assistant, NCIRS

Seize the moments: missed opportunities to immunize at the family practice level

Turner N, Grant C, Goodyear-Smith F, Petousis-Harris H
Family Practice 2009;26(4):275-8
Link to abstract

Missed opportunities (MOs) are an important factor contributing to incomplete immunisation. This study described the frequency and characteristics of MOs within a New Zealand primary health care setting and estimated their effect on incomplete immunisation. It involved an audit of medical records of randomly selected children aged less than 2 years from 62 practices in Auckland, New Zealand. The study found that MOs occurred in 97% of practices. The MOs were more common with acute illness visits and contraindications for immunisation were present in 5% of visits. In addition, children with MO visits were 3 times more likely to be incompletely immunised. This audit concluded that MOs to vaccinate children occurred in most practices and that directives should focus on the practitioner and the practice system to reduce MOs.

Presented by Dr Aditi Dey , Epidemiologist, NCIRS

Immuno-biology of HPV infection and how HPV vaccines work

Guest speaker: Professor Margaret Stanley, Department of Pathology, University of Cambridge

Key highlights :

Human papillomaviruses 
Human papillomaviruses (HPV) are small DNA viruses that are species specific and epitheliotropic. More than 100 HPV types have been cloned and characterised from clinical biopsies of cutaneous or mucosal surfaces. 

About 30 to 40 HPV types infect the anogenital tract of both men and women. In these sites the viruses fall into two groups: low risk viruses such as HPV 6 and HPV 11 that cause genital warts and recurrent respiratory papillomatosis, as well as contributing to low grade cervical, vaginal and vulval lesions; and high risk HPVs which are associated with anogenital cancers. There are ~15 oncogenic HPV types, the most important of which are HPV 16 and HPV 18, causing ~70% of cervical cancers worldwide.

Natural history of infection 
After infection there is a latent period between infection and HPV DNA detection. This interval is of variable duration extending for weeks, months or even years and is probably related to the dose of infectious virus. 

Eventually the virus is kick started into action, virus replication is initiated, viral DNA can be detected in cervical swabs or genital skin scrapes and clinical lesions become evident. Cycles of virus replication, assembly and shedding, apparently in the absence of an immune response, then continue for a variable period that may extend for at least 12–18 months for the high risk HPV types. but Eventually a cell mediated immune (CMI) response is initiated with cytotoxic effectors accompanied or followed by seroconversion and antibody to the major coat protein of the virus L1. The vast majority of infected individuals – 80–90% of women – make a good CMI response, they become HPV DNA negative and in general remain refractory to re-infection by the HPV type against which they have mounted a successful immune response. A minority of women, 10–20%, make an inadequate CMI response and remain DNA positive with persistent virus infection. This group of women are at risk for progression to high grade cervical, vulval and vaginal intra-epithelial neoplasia (CIN2/3, VIN3, VaIN3), and therefore invasive cancers, at these sites.

HPV antibodies 
In natural infections, neutralising antibodies are type specific. The average time to seroconversion for HPV 16 infections is 8–9 months after the first detection of HPV DNA and apparently only 50–70% of women with incident infection seroconvert. Peak serum antibody concentrations are low but at least 25% of women continue to have detectable antibody over a 10 year period post seroconversion. Nonetheless evidence from animal infections show that this neutralising antibody is protective and passive immunisation experiments in dogs, with purified immunoglobulin G from animals post wart regression, demonstrate that the immunised animals are protected against viral challenge and disease.

It is important to note that HPV serology is not standardised and there is no immune correlate of protection for HPV antibodies.

Prophylactic HPV vaccines 
Prophylactic HPV vaccines are sub unit protein vaccines comprised of the L1 coat protein assembled into virus like particles (VLPs). VLPs are empty protein shells almost identical to the virus particle. Passive immunisation experiments using the dog and rabbit models showed that the antibodies generated after VLP immunisation protected against viral challenge and wart formation.

Extensive clinical trials have served to confirm the efficacy, immunogenicity and safety of HPV vaccines. 

While the passive transport of serum antibodies into the squamo-columnar junction of the cervix could explain the mode of action of VLP antibodies, this would not explain protection at keratinised surfaces of the vulva, penis and peri-anal skin. Recent studies have shown that HPV infection requires micro abrasion of squamous epithelium that results in epithelial denudation but retention of basement membrane. The microwound would result in an immediate serous exudate rich in plasma proteins including serum IgG, phagocytes, and immunocytes including memory B cells. Virus neutralisation and a recall response would ensue.

Studies have also examined the proposed mechanism of virus entry. HPV initially binds by a primary receptor to this exposed basement membrane before entry to keratinocytes. This is a protracted process extending over 24–48 hours during which virus capsid undergoes conformational change. The mechanism by which neutralising antibodies to HPV prevent viral entry is via binding to capsid, and preventing basement membrane attachment and the conformational distortion which is essential for successful entry. These antibodies neutralise at extremely low concentrations – 10 -12M

Duration of protection
Human subjects involved in an extension study with the quadrivalent HPV vaccine demonstrated immune memory when given an antigen challenge 5 years after the vaccination course. This is reassuring but needs to be supplemented with long term follow up of vaccinated cohorts.

Further reading
Stanley M. Immunobiology of HPV and HPV vaccines. Gynecologic Oncology 2008;109:S15-S21

The effect of 23-valent pneumococcal polysaccharide vaccine on immunological priming induced by 7-valent conjugate vaccine in asplenic subjects with beta-thalassemia

Orthopoulos GV, Theodoridou MC, Ladis VA, et al. 
Vaccine 2009;27(3):350-4
Link to abstract 

This is the first study to evaluate the effect of 23-valent pneumococcal polysaccharide vaccine (PPV) on 7-valent pneumococcal conjugate vaccine (PCV)-induced immunological priming in splenectomised patients with ß-thalassemia. The results suggest that one dose of PPV following PCV does not affect PCV priming in splenectomised subjects with ß-thalassemia which is congruent with the fact that combined PCV/PPV schedules have been recommended for subjects with sickle cell disease and HIV infection. However, combined schedules should not be used for those already vaccinated with multiple PPVs prior to PCV, in order to avoid further overloading with polysaccharide antigens that cause hyporesponsiveness; repeated PPV immunisations are required to maintain the benefit of extended protection but the biological significance of hyporesponsiveness induced by such practice is not clear so far. There is an urgent need for the new generation of pneumococcal vaccines offering long-lasting protection against most pathogenic serotypes for better protection of high risk individuals.

Presented by Dr Deepika Mahajan, Research Officer, NCIRS

Do they accept compulsory vaccination? Awareness, attitudes and behaviour of hospital health care workers following a new vaccination directive

Seale H, Leask J, MacIntyre CR
Vaccine 2009;27(23):3022-5
Link to abstract 

Achieving high vaccination rates among health care workers (HCW) is an ongoing challenge. In 2007, the state of New South Wales, Australia, instituted a policy directive with compulsory provisions for health care workers to be vaccinated. This study sought to identify staff awareness and attitudes in the early phase of implementation. It involved a self-completed paper-based or electronic survey of HCWs in two tertiary referral teaching hospitals in Sydney, Australia, in 2007. A total of 894/1200 completed the paper survey, while a further 185 completed it online. Of the 1079 respondents, 60% (646/1079) were aware of the policy directive but only 10% (63/646) described the specific requirements. Seventy-eight per cent supported the policy; 13% neither supported nor opposed it; and 4% opposed it. This survey provides an early, broad indication of the level of understanding and the attitudes of the HCWs towards the new directive. 

Presented by Dr Holly Seale, Associate Lecturer, School of Public Health and Community Medicine, UNSW

Informing adolescents about human papillomavirus vaccination: what will parents allow?

Vallely LA, Roberts SA, Kitchener HC, Brabin L
Vaccine 2008;26(18):2203-10
Link to abstract

This study evaluated a film that educated students in the UK about HPV and HPV vaccine. The study was well-done, though it would be interesting to determine what happened in the schools as a result of watching the film. The researchers provided information about knowledge and attitudes after watching the film, but we don't know if behaviour was affected. For example, did less girls opt out of receiving the HPV vaccine during the school vaccination day because of the film? The study is highly relevant to the Australian context since Australia has a school-based HPV vaccination program. The AU program doesn't currently provide education directly to girls themselves, though it does provide information sheets for parents/guardians. It is possible that a film, such as the one described in this study, would be a valuable tool for the AU program.

Presented by Dr Spring Cooper, Senior Research Officer, NCIRS