Title: Evaluating the effect of 'MenB' vaccination on meningococcal carriage
Funder: Department of Health and Social Care

Abstract: Background In 2015 the United Kingdom was the first country to introduce routine immunisation with the 4CMenB (Bexsero), a protein-based vaccine developed to prevent capsular group B meningococcal (MenB) disease. This vaccine is given at 2, 4 and 12 months of age, with early results indicating 83% effectiveness at preventing MenB disease. However, this approach is designed only to protect those receiving the vaccine ( direct protection ) and will not reduce rates of MenB disease in those born before the 1st May 2015. This contrasts with the use of conjugate polysaccharide vaccines that target the capsular antigen, such as the A, C, W and Y (MenACWY) vaccine that was introduced to the adolescent immunisation schedule in 2015, in response to the emergence of a hyperinvasive MenW strain. Such vaccines are known to affect asymptomatic carriage and this campaign was designed, not only to provide direct protection to the immunised teenagers, but also to reduce the carriage and transmission of MenW meningococci, thereby providing herd immunity and protecting the wider community. Such an approach could also be employed for 4CMenB or another licensed MenB vaccine rlp2086, however, unlike conjugate polysaccharide vaccines, it is unknown whether immunisation with the MenB vaccines has any impact of oropharyngeal carriage of meningococcus, hence the urgent the need for a study of sufficient power to answer this question definitively. Aims To demonstrate whether immunisation with 4CMenB or rlp2086 reduces oropharyngeal carriage of potentially invasive meningococcal isolates. Research plan The prevalence of oropharyngeal carriage of invasive meningococcal isolates will be surveyed in 24,000 secondary-school students. One third of these students will receive 2 doses of 4CMenB six months apart. another third will receive two doses of rlp2086 6 months apart, and teh remaining third 4CMenB at the end of the study. Meningococcal carriage will be re-evaluated in all students 12 months after their first swab to determine if immunisation with 4CMenB has reduced the prevalence of invasive meningococci. This study will be delivered across at least 14 sites, each recruiting through multiple secondary schools. Research Team The applicants represent a unique combination of expertise in delivering and analysing studies evaluating meningococcal immunisation and carriage. Members of this team undertook the UKMenCar1-3 studies (1999-2001), which definitely established the effect of meningococcal conjugate polysaccharide vaccines on meningococcal carriage and the 2014-2015 UKMenCar4 study, which evaluated meningococcal carriage in 20,000 secondary school students. The network of sites that delivered UKMenCar4 will be re-deployed for this new study. The study will be coordinated by the Oxford Vaccine Group, a UKCRC registered clinical trial unit (PCVCCTU) with experience of leading multi-centre clinical trials. The University of Oxford has the capacity and willingness to sponsor this clinical trial. This study will be informed by emerging data from Bristol, which has conducted the BrisMenNHC study as a longitudinal follow-on to UKMenCar4 in approximately 900 UKMenCar4 participants. This site is also running the 'SPIT' study studying meningococcal carriage in throat swabs and saliva samples in 400 sixth form students given 4CMenB. Microbiological analysis will be performed by the laboratories of Professors Borrow and Maiden, the latter providing high-resolution, high-throughput characterisation of the Neisseria isolates obtained and data analysis and dissemination. The design of the study and interpretation of results in context of modelling impact will be informed by the epidemiological expertise of DrsTrotter and Christensen. Potential impact Data from this study will directly inform the UK immunisation policy. If immunisation with 4CMenB or rlp2086 is found to reduce meningococcal carriage this would support an adolescent MenB immunisation programme to reduce meningococcal disease across all ages in a cost-effective manner.

Lay abstract: In the United Kingdom, children die more commonly from invasive meningococcal disease than any other infectious disease. The germ responsible (a bacteria known as meningococcus) can live in the throat without causing symptoms ( carriage ), but can occasionally become invasive, infecting the fluid around the brain (causing meningitis) or the bloodstream (septicaemia). Since 2015 a vaccine against the type of meningococcus that causes most disease in the UK (group B, or MenB) is given routinely at 2, 4 and 12 months of age, and as a result the numbers of cases of MenB disease in the immunised age group have halved. However, very few people born before May 2015 will have received this vaccine (known as 4CMenB), and are therefore still vulnerable to this infection. One way to provide broader protection in the community would be to stop the spread of the bacteria from one person to another. Some vaccines can achieve this by reducing the number of people harbouring the bacteria in their throat (carriage). For meningococcal infections the ideal age group for immunisation to achieve this would be teenagers, as they have been consistently shown to exhibit the highest rates of carriage in the UK (currently ~7%); however it is unclear whether immunisation with 4CMenB can reduce carriage of meningococcus. We therefore propose a study enrolling 24 000 adolescents in year 12 at school (approximately 16 to 18 years). One third of these participants would receive the 4CMenB vaccine, one thord woudl receive an alternative MenB vaccine (rlp2086) and one third would be unimmunised controls . Throat swabs would be taken from all participants at the beginning of the study, and again 12 months later, to see if those that had received the vaccines had lower rates of carriage of MenB than the controls. The study will be conducted at approximately 14 sites across the UK, and allocation to immunised or control groups would be performed on a site-by-site basis. Such a study would provide a definitive answer as to whether immunising adolescents with MenB vaccines could protect the whole community against this deadly disease in a highly efficient manner.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION