Day one abstracts

Socio/psychological/cognitive sequelae and follow-up care - Day one 09:55

Following welcome improvements in outcome of critical illness in children, more emphasis has been placed on the understanding of the consequences of severe illness in children regarding their long-term prognosis. We and others have noticed that significant effects on psychological, psychosocial and educational performance are commonly seen following intensive care admission.

This talk will attempt to explore factors associated with outcome following intensive care admission for critical illness in children, focusing on meningococcal disease and meningitis.

Read Dr Nadel's biography here

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Orthopeadic sequelae of meningococcal disease and their management - Day one 10:15

This is an overview of the current concepts in the management of children who have had orthopaedic sequelae following meningococcal septicaemia.

The talk will initially highlight the management in the hours after onset and discuss controversies including the role of fasciotomies during this period.

The immediate management of the limb once the patient has been stabilised will be outlined, including strategies for amputation.

The longer term management will be described, including reconstruction for the consequences of ischemic growth arrest and strategies to improve prosthetic wear including soft-tissue transfers, segmental lengthening and limb realignment.

Mr Fergal Monsell is Consultant Paediatric Orthopaedic Surgeon at the Royal Hospital for Children, Bristol. biography here

Hearing loss after meningitis: assessment and management - Day one 10:35

Meningitis resulting in labyrinthitis and its associated hearing loss was first described in the 1860 with Adam Politzer, the eminent Viennese otologist, providing a definitive description of the clinical presentation in 1882. This led to the recognition of the temporal bone as a potential conduit of infection from the upper aero-digestive tract to the meninges. Human temporal bone histopathological studies have provided invaluable information about the possible access routes, both in the normal temporal bone but also in cases of congenital anomalies of the inner ear (eg the Mondini deformity, common cavity anomalies etc) which render patients particularly vulnerable to bacterial meningitis, sometimes in recurring bouts. Despite major advances in the primary prevention of meningitis and the use of more effective antimicrobial agents and corticosteroids, hearing loss remains a significant complication of meningitis. The hearing loss may be conductive (usually attributable to a middle ear effusion) or sensorineural, the latter being either temporary or permanent. The incidence of profound sensorineural hearing loss is approximately 1%, although the range across studies is great due to sampling errors in small sample sizes. Best clinical practice would suggest that all children and adults be formally tested audiologically following bacterial meningitis. A major consequence of meningitis on the inner ear is bony obliteration (labyrinthis ossificans) which can obliterate the fluid spaces of the inner ear at any time following the meningitis, making consideration of cochlear implantation a matter of urgency. In severe instances of obliteration, auditory brain-stem implantation may represent the only means of hearing restoration. Cochlear implants have transformed the outcomes for children with profound deafness following meningitis and are now considered a priority group for bilateral cochlear implantation. Expeditious referral of children who experience severe or profound hearing loss following meningitis to cochlear implant centres is imperative to achieve the best outcomes for these patients.

Read Prof O'Donoghue's biography here

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Best use of conjugate vaccines: waning of infant protection from accelerated schedules; herd immunity; implications for developing countries using EPI schedules? - Day one 11:50

Conjugate vaccines, where the bacterial polysaccharide capsule is attached to an immunogenic carrier protein, were first used in the UK in 1992, with the introduction of Haemophilus influenzae type b (Hib) vaccines. Immunisation programmes offering protection against Neisseria meningitidis serogroup C (MCC) and seven serotypes of Streptococcus pneumoniae (PCV7) were subsequently introduced in 1999 and 2006 respectively. Two major advantages of conjugate vaccines over plain polysaccharides are that they are immunogenic and effective even in young children and that they are able to prevent pharyngeal carriage and thus interrupt onward transmission. As a result, these vaccines have had a major impact on serious invasive disease in both immunised children, and the population as a whole.

Ongoing, high-quality laboratory-based surveillance has been essential and has facilitated the work of epidemiologists, microbiologists, immunologists and mathematical modellers in building a comprehensive understanding of the way in which these vaccines work. Based on the UK experiences with conjugate vaccines, this talk will review the public health impact of these immunisation programmes, lessons learned about schedules and herd immunity, the similarities and differences between the three vaccines, and the implications of these findings for the use of conjugate vaccines in other settings and against new antigens.

Read Dr Trotter's biography here

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Recruitment of Factor H by Neisseria Meningitidis and Streptococcus pneumoniae:immune evasion and vaccines - Day one 12:15

All pathogens must replicate successfully in their hosts to cause disease. To achieve this, bacteria have to avoid being killed by the host immune system. The complement system is critical for protecting individuals against Neisseria meningitidis and Streptococcus pneumoniae, leading causes of bacterial meningitis worldwide. Complement can direct destruction of bacteria by phagocytic cells, and directly cause their lysis and death. However the meningococcus and the pneumococcus have evolved remarkably sophisticated mechanisms which protect them against complement mediated killing. For instance, both these pathogens can recruit human complement regulatory proteins (such as factor H and C4BP) to their surface to inactivate the complement system. This not only promotes their virulence, but needs to be taken into consideration when developing assays to assess the efficacy of vaccines. Complement regulators often bind to immunogenic proteins on invading microbes, so defining interactions between this aspect of the immune system and important human pathogens such as N. meningitidis and S. pneumoniae could help in vaccine design.

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Read Prof Tang's biography here

Changes in pneumococcal serotypes in England and Wales before and after introduction of PCV7 - Day one 14:20

The Respiratory and Systemic Infection Laboratory and the Immunisation Department of the Health Protection Agency Centre for Infections -with input from all parts of the NHS and the Oxford Vaccine Group and clinical laboratories in particular- have been undertaking the surveillance of invasive pneumococcal disease, together with serotype characterisation of invasive disease isolates from epidemiological year 1996/97 to date.

The proportion of all invasive pneumococcal disease (IPD) for which serotype has been determined has increased steadily over that time period. Following extensive efforts by the HPA to encourage submission of isolates for serotyping the proportion of cases with serotype determined has risen from 36% of all IPD in epidemiological year 1996/97 to 75% in 2005/06 and 76-80% in more recent years. Since 2004/05 serotype has been determined for ~90 % of all reported paediatric (age 5 or less) IPD covering two years in advance of introduction of PCV7 and all the years since then.

As expected there have been significant shifts in serotype distribution following the introduction of PCV7 in September 2006 with major declines in vaccine serotypes and increases in non-vaccine serotypes in all age groups. These changes are shown graphically and updated regularly, on the pneumococcal pages of the HPA website. See; http://www.hpa.org.uk/HPA/Topics/InfectiousDiseases/InfectionsAZ/1203008863939/

However, not all serotype change is vaccine driven, there was evidence of shifts in serotype distribution for both vaccine and non-vaccine types amongst IPD cases in the years prior to PCV7 introduction. For example serotype 14 (included in PCV7) was declining and serotype 1 (not in PCV7) was increasing prior to PCV7 use in the population. The presentation will cover temporal trends in both vaccine and non-vaccine types before and after PCV7 introduction into the UK immunisation schedule.

Read Dr George's biography here

Prospects for preventing invasive pneumococcal disease with conjugate vaccines beyond PCV7, including evidence for use in a 2 + 1 immunization schedule - Day one 15:10

The 7-valent pneumococcal CRM197 protein conjugate vaccine (PCV7, Prevenar®) was licensed based on clinical efficacy in preventing invasive pneumococcal disease (IPD), pneumonia and acute otitis media when administered to infants as a four-dose schedule (“3+1”). The effectiveness of Prevenar® to prevent these clinical manifestations of pneumococcal disease has been subsequently demonstrated when given as part of national vaccination programs, either as a “3+1” schedule or an alternative three-dose immunisation schedule (“2+1” or “3+0”). To increase serotype coverage globally, a 13-valent pneumococcal CRM197 protein conjugate vaccine (PCV13) including serotype 1, 3, 5, 6A, 7F and 19A, was developed. As controlled efficacy trials are no longer feasible, the clinical development of PCV13 was based on head to head immunogenicity comparison with Prevenar® used as a comparator which has previously demonstrated efficacy. Phase III non-inferiority trials compared the serotype-specific IgG antibody response, proportion of infants achieving the threshold of 0.35 mcg/mL (the reference antibody concentration recommended by the World Health Organization) and IgG GMCs. In a pivotal trial using a “3+1” schedule (2, 3, 4, 11 months), PCV13 non-inferiority was generally demonstrated for the 7 serotypes common to Prevenar® and PCV13. Although slightly lower, IgG GMCs for PCV13 were non-inferior to Prevenar®. In addition, the functional activity of vaccine-induced antibodies (measured with an opsonophagocytosis assay) was established, as well as the evidence of the induction of immunological memory following the final (booster) dose of conjugate vaccine. Non-inferiority was met for the six additional serotypes based on the proportion of infants achieving an IgG antibody concentration ≥ 0.35µg/mL and IgG GMCs achieved one month after the primary series. Functional antibody responses were demonstrated among PCV13 recipients for each of the 6 additional serotypes. 

Immunogenicity of PCV13 given according to a “2+1” schedule was also evaluated. For the 7 common serotypes, the proportions of IgG responders at ≥ 0.35µg/mL were generally comparable one month after the primary series, except for serotype 6B. Similarly good responses were noted for all 7 serotypes after the booster dose at 11-12 months. For the additional serotypes, functional antibody response was noted in at least 88% of recipients following the first 2 doses of PCV13. Antibody levels achieved after the booster dose are comparable to those after a “3+1” schedule. 

PCV13 offers the potential to broaden the immune protection against pneumococcal disease. It can be anticipated that, when given at a “2+1” schedule in a national immunisation programme, PCV13 will be as effective as Prevenar®.

Read Dr Fritzell's biography here

Impact of PneumoADIP: Progress on update of pneumococcal vaccines in development - Day one 16:30

The World Health Organization (WHO) estimates that 1.6 million people die every year from pneumococcal infections – primarily pneumonia and meningitis – including >800,000 children under five years old. Pneumococcal disease is preventable by vaccination. Unfortunately, it has historically taken 15-20 years for new vaccines to reach children in developing countries.

PneumoADIP is a dedicated team of experts and specialists based at the Johns Hopkins Bloomberg School of Public Health and is supported by the GAVI Alliance (GAVI). Our mission is to improve child survival and health by accelerating the evaluation of and access to new, lifesaving pneumococcal vaccines for the world’s children. PneumoADIP accomplishes its mission by working with countries, donors, academia, international organizations, and industry to develop effective public-private partnerships directed towards accelerating introduction. This greater awareness about the disease and vaccine, support for surveillance, and availability of GAVI funding have all contributed to accelerating vaccine introduction. WHO, UNICEF, and others have supported countries in developing vaccine plans, financing strategies, and cold chain and systems capacity required for successful applications.

These collaborative efforts have led us to the introduction of pneumococcal vaccines in the poorest countries in 2009 – at least ten years faster than historical precedents. Based on the progress being made now and the foundation it has set for the future, we project that accelerated pneumococcal vaccine introduction could prevent ~ 7 million deaths by 2030.

Some of the major changes we have seen between 2003-09 include:

• WHO’s recommends routine pneumococcal vaccination in all countries
• GAVI Alliance endorses first Investment Case for Pneumococcal Vaccines
• Global donors pledging US$1.5 billion for an Advance Market Commitment for pneumococcal vaccines
• The commitment of multinational and emerging vaccine manufacturers to develop and supply pneumococcal vaccines to low-income countries
• Pneumococcal vaccine introduction in 2 GAVI eligible countries.
• The submission of applications from 20 countries for GAVI support for introduction, 12 of which have already been approved.
• Expression of interest from 31 of the 72 GAVI eligible countries to introduce pneumococcal vaccination as part of their public health efforts

Continued progress with pneumococcal conjugate vaccines will require sustained political will and funding, delivery systems to reach all children who need the vaccine, surveillance to document the vaccine’s impact, and research to continue finding improved ways to prevent and treat pneumococcal disease.

You can read Dr Levine's biography here

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Progress on pneumococcal protein vaccines - Day one 16:00

The goal of PATH’s Pneumococcal Vaccine Project is to accelerate the development of promising pneumococcal vaccines and ensure their affordability, availability, and use in developing countries. As part of this project, PATH is developing a portfolio of potential vaccine candidates with a particular emphasis on “common protein” vaccines. Vaccines containing proteins that are common to all pneumococcal serotypes could provide broad and affordable protection to children worldwide. Our current protein vaccine partnerships range from novel methods of antigen discovery to well characterized vaccine candidates that have provided protection in multiple animal models and are currently in early stages of clinical evaluation. A second strategy involves development of a killed, whole cell vaccine, also designed to offer broad serotype-independent coverage coupled with low manufacturing costs and ease of administration. PATH is also exploring strategies to incorporate common protein antigens into a limited valency pneumococcal conjugate vaccine (PCV). This hybrid approach is designed to take advantage of the regulatory path established for licensure of new PCVs and to offer the further benefit of broader coverage by adding a pneumococcal protein antigen. In addition to supporting the development of innovative vaccine candidates, PATH is implementing support for research designed to meet general needs within the field of pneumococcal vaccine research. These include cataloging pneumococcal strain collections, identifying models or assays for use in preclinical testing of potential vaccines, defining the natural human immune response to pneumococcal protein antigens, improving diagnostic tools, and identifying production processes so that vaccines are affordable for distribution by public health systems in low-income countries.

Read Dr Alderson's biography here

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Prevention of invasive pneumococcal disease and meningitis with PHiD-CV when used according to a 2+1 schedule - Day one 15:10

Synflorix™ (PHiD-CV) is a mixed-carrier pneumococcal conjugate vaccine (PCV), containing polysaccharides of 10 pneumococcal serotypes. Eight serotypes (1, 4, 5, 6B, 7F, 9V, 14, 23F) are conjugated to a recombinant non-lipidated form of Protein D of non-typeable Haemophilus influenzae . Serotype 18C is conjugated to tetanus toxoid and 19F to diphtheria toxoid. 

As for other conjugate vaccines, new PCVs are licensed based on the comparison to a licensed vaccine with proven efficacy of the percentage of vaccinees reaching a reference antibody concentration (0.2 μg/mL with GSK's 22F-ELISA) and demonstration of immunological memory and biological functionality of the induced antibodies (opsonophagocytic activity, OPA). Previous studies demonstrated that high percentages of PHiD-CV vaccinees achieved the ELISA threshold and/or OPA titers &ge8 following 3-dose primary vaccination in infants. In addition, robust antibody and OPA booster responses, indicative of immunological memory, were observed following booster vaccination in the second year of life. 

Efficacy data for PCVs are based on 3-dose primary vaccination with or without booster dose. However, several countries have introduced the 7-valent-PCV (PCV7; Prevenar™/Prevnar™) using a 2+1 immunization schedule and high effectiveness against IPD is now being reported from countries such as the UK, Norway and Canada, despite reduced antibody responses for some serotypes (mainly 6B and 23F). Two studies assessed PHiD-CV immunogenicity after two doses of primary vaccination: study-002 (NCT00307034) assessed a 3, 5 and 11-12 month (2+1, N=153) schedule, versus a conventional 3, 4, 5 and 11-12 month (3+1, N=153) schedule and study-011 (NCT00334334) assessed immunogenicity of PHiD-CV (N=156) and PCV7 (N=146) 2 months post-dose-2 (2, 4 month schedule).The percentages of participants with antibody concentrations ≥0.2 μg/mL were within the same ranges after 2-dose and 3-dose priming for each of the 7 common serotypes except 6B and 23F, and post-dose-2 responses were within the same ranges for PHiD-CV and PCV7 (Table). Booster responses following PHiD-CV at 11-12 months were observed for all 10 serotypes, but the percentage of participants with antibody concentrations ≥0.2μg/ml remained lower for serotype 6B (88.5% - study-002: 2+1, (data not shown)).

 

	%22F-ELISA antibody concentration ≥ 0.2 μg/mL				% OPA ≥ 8
	Study-002		Study-011		Study-002		Study-011
	PHiD-CV Post2	PHiD-CV Post3	PHiD-CV Post2	PCV7 Post2	PHiD-CV Post2	PHiD-CV Post3	PHiD-CV Post2	PCV7 Post2
1	97.4	98.7	95.8	4.2	60.8	62.9	48.8	0.0
4	98.0	99.3	98.7	99.3	100	99.2	97.8	95.6
5	96.1	100	96.5	2.1	82.6	90.8	74.6	0.0
6B	55.7	63.1	64.1	30.8	74.4	88.9	63.0	35.2
7F	96.7	99.3	98.6	6.4	90.6	98.5	96.8	0.0
9V	93.4	99.3	96.1	96.6	100	100	98.5	99.3
14	96.1	100	99.4	97.9	98.5	100	97.1	93.3
18C	96.1	99.3	87.8	97.3	82.8	96.2	59.8	77.0
19F	92.8	96.1	96.2	99.3	87.0	93.8	84.3	67.9
23F	69.3	77.6	75.0	74.7	86.3	97.7	97.1	87.8

Post-2= one (study 002) or two (study 011) months after 2nd primary dose; Post-3= one month after 3rd primary dose

These studies are also the first to report functional OPA responses following a 2-dose primary schedule. The observed percentages of children with OPA titers ≥8 were within the same ranges post-dose-2 and post-dose-3 for serotypes 1, 4, 9V and 14, but were lower for other serotypes (Table). Low OPA titers were measured for some serotypes post-dose-2 of PCV7 in study-011. Despite rising substantially, OPA titers following PHiD-CV booster remained lower in the 2+1 compared to the 3+1 group (data not shown). Conclusion: In line with other PCV-studies using the 2+1 schedule, lower anti-pneumococcal responses were observed for several serotypes when PHiD-CV was used according to the 2+1 compared to the 3+1 schedule. Comparative data suggest that post-dose-2 ELISA and OPA responses following PHiD-CV vaccination are within the same ranges as post-dose-2 responses for PCV7 for the 7 common serotypes. Synflorix is a trademark of the GlaxoSmithKline Group of companies and Prevenar/Prevnar is a trademark of Wyeth Lederle.

Read Dr Schuerman's biography here

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Impact and challenges of the Hib initiative - understanding and communicating burden of disease - Day one 17:00

This program included five phase two trials (including one in pregnant women) and one large phase three efficacy trial. This trial, which was designed and lead by Kim, was the first to demonstrate the efficacy of Hib vaccine against pneumonia, and in doing so it gave the first real estimate of the contribution of Hib to the burden of pneumonia in a developing country setting. This design, which incorporated elements of efficacy and effectiveness studies, became the template for future pneumococcal vaccine studies and was the first trial known as a vaccine probe study.

In that role he established the pneumococcal trialists working group which established agreed endpoints for vaccine trials for which pneumonia is an endpoint. All subsequent vaccine studies, including later Hib studies, employed the pneumonia definitions established by this group.

Research undertaken by this group in Fiji has established the burden of disease due to pneumococcus, rotavirus, HPV and Group A Streptococcus. The latter program has been undertaken as part of a larger program to develop and evaluate a Group A Streptococcal vaccine suitable for the developing world. Since 2001 a program of research in Fiji has undertaken a complex phase 2 pneumococcal vaccine trial designed to evaluate alternative strategies for pneumococcal vaccine use that may be more appropriate in developing countries. He has also established pneumococcal immunology and microbiology laboratories, with funded programs of research to investigate the impact of pneumococcal vaccination strategies.

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Read Prof Mulholland's biography here