Title: National Immunisation Schedule Evaluation Consortium (NISEC)
Funder: Department of Health and Social Care

Abstract: Background Immunisation is central to the health of every UK resident. It is essential that the routine immunisation schedule be employed in a way that achieves optimal impact for minimum cost. Means of achieving this include combining vaccinations at the same visit or by allowing different vaccines against the same disease target to be used interchangeably, facilitating procurement of a sustainable supply. The consortium will have the ability to evaluate novel schedules rapidly and to respond to evolving changes in disease epidemiology and outbreaks. Aims To respond to research needs prioritised by the Department of Health and/or the JCVI, including any emergent threat from infectious disease (e.g. influenza pandemics). Current research priorities identified by the consortium that are likely to be relevant include: incorporation of vaccines against Hepatitis B virus (HBV) into the infant immunisation schedule the potential for mixed schedules of HPV vaccines to achieve an expanded breadth of protection against cervical cancer while minimising incremental costs the influence of maternal pertussis immunisation on the persistence to preschool age (3 &frac12; years) of antibodies induced by infant immunisation Research Plan and methods of investigation To answer these questions the suggested research plan is: a comparison of the immunogenicity of two combination diphtheria-toxoid, tetanus-toxoid, acellular pertussis, Haemophilus influenzae type b, inactivated polio and Hepatitis B vaccines (trade names Vaxelis and Infanrix-hexa) a randomised comparison of the immunogenicity of three HPV vaccine regimens incorporating the recently licensed nonavalent HPV vaccine given at 6 month intervals: i) HPV2 followed by HPV9; ii) HPV9 followed by HPV2; iii) HPV9 followed by HPV9. An extension study evaluating vaccine induced antibodies at 3 &frac12; years of age following immunisation of infants born to mothers receiving either Repevax, Boostrix, or no pertussis vaccine, in pregnancy As outlined above alternative research priorities may be identified and will be addressed in a flexible manner as needed. Research team This collaboration will combine the expertise, clinical trial capacity and laboratory facilities of Public Health England (including UCL Great Ormond Street Institute of Child Health) and the UK Paediatric Vaccine Group (UKPVG, consisting of the Oxford Vaccine Group, St George s Vaccine Institute, Bristol Children s Vaccine Centre, the University of Southampton and Imperial College). The Oxford Vaccine Group, University of Oxford will provide the administrative lead with responsibility for financial management, clinical trial databases, monitoring and report submission. Public Health England (PHE) will provide statistical support and responsibility for laboratory assays. Across the consortium there is capacity for clinical trials in healthy paediatric, adolescent, maternity, adult and elderly populations, as well as high-risk child and adult populations and a proven record in delivering expedited large-scale studies in the event of emergent health crises. As PHE undertakes the post-marketing surveillance of vaccine preventable diseases, provides scientific secretariat to the JCVI, procures the vaccines for the NHS programme, co-ordinates the implementation of the English programme, provides all clinical and technical guidance to NHS commissioners and providers and undertakes the public communication activities, having PHE in the leadership of the consortium will ensure that the research remains flexible to the needs of the programme. The link between direct evaluation of programme impact undertaken by PHE and the results of immunogenicity studies conducted by NISEC will sustain the reputation of the UK programme as one of the most innovative and evidence-based in the world. Potential Impact It is expected that the above body of work will directly contribute to changes in the UK immunisation schedule across all ages, providing evidence to optimise the cost-effective use of new and existing vaccines. These in turn are expected to lead to improved protection against vaccine-preventable infectious diseases.

Lay abstract: NISEC will conduct studies to determine the best use of vaccines in the United Kingdom. The applicants within this consortium have previously shown the capacity and adaptability to respond to urgent research questions &ndash; for example in response to national outbreaks of infection or when new vaccines become available. NISEC has identified the following research questions of current relevance: 1) Hepatitis B virus vaccines The UK Joint Committee on Vaccines and Immunisation (JCVI) has recommended routine infant immunisation against hepatitis B virus to reduce chronic liver disease and cancer. Two vaccines (Vaxelis and Infanrix-hexa) could potentially enable this without extra vaccine injections by incorporating the hepatitis vaccine into a 6-in-1 infant vaccine, building on the current 5-in-1 vaccine against diphtheria, tetanus, polio, Haemophilus influenzae type b and whooping cough. It is important to conduct a head-to-head study to determine whether both vaccines are suitable for inclusion in the UK schedule; if this shown then this will allow greater flexibility in vaccine purchasing, which may be cost saving and ensure that vaccine supply for the UK population is more secure. 2) Human papilloma virus (HPV) vaccines Since 2008 all 12 to 14 year old girls in the UK have been offered vaccines against either 2 (HPV-2; Cervarix&reg;) or 4 (HPV-4; Gardasil&reg;) common types of HPV, an important cause of cervical cancer. A new vaccine against 9 types of HPV (HPV-9; Gardasil&reg;9) has been licensed that could further reduce cases of cervical cancer. NISEC propose to conduct a study comparing the licensed 2 dose schedule of HPV-9, with mixed schedules that use a single dose of HPV-2 and HPV-9, potentially delivering the benefits of the latter vaccine in a more cost effective manner. 3) Maternal immunisation Immunising pregnant women against whooping cough has reduced the rates of this disease in infancy, but may also slightly reduce the immune responses of infants to their own vaccines. This may mean that the age that pre-school booster doses are given should be given earlier. Accordingly, NISEC will compare the levels of vaccine-induced antibodies in 3 year-old children born to immunised and unimmunised mothers.

Research activity codes: 3.4 VACCINES
Health categories: CANCER AND NEOPLASMS;INFECTION