The Effect of Live Attenuated Inactivated Influenza Vaccine on Experimental Human Pneumococcal Carriage Study

The investigators are interested in examining the effect of the Live Attenuated Influenza (flu) Vaccine (LAIV) upon nasal carriage of bacteria called Streptococcus pneumoniae (also known as pneumococcus). The nasal spray is a live attenuated vaccine which means that it has weakened virus that does not cause disease. This vaccine is licenced in the United Kingdom for children and adolescents from 2 to 18 years of age.

Pneumococcus can commonly be found harmlessly inhabiting the nose where it does not cause any problem (pneumococcal colonisation). About 10% of adults carry pneumococcus at any one time, and almost all adults experience an episode of carriage at least once per year. Carriage acts as a natural vaccine, boosting immunity against pneumococcal infection in adults and children.

During influenza there is an increase in the burden of pneumococcal pneumonia. We have studied the effects of pneumococcus for many years and have developed a programme in which we can nasally inoculate healthy participants with a dose of pneumococcus and achieve a reproducible carriage rate. The investigators would now like to use this model to investigate the effects of the nasal influenza vaccine upon pneumococcal carriage and to better understand how influenza infections lead to increased susceptibility to pneumonia.

Pneumococcal disease in young adults is rare - less than 10 cases per 100,000 people per year. When pneumococcus does cause problems, usually in young children or elderly people, it can be very serious as it is responsible for diseases such as pneumonia, sepsis and meningitis, which kill millions of children around the world each year.

Secondary bacterial infections such as pneumococcal pneumonia are a leading cause of death during influenza endemics. Individuals recently infected with influenza become more susceptible to pneumonia, an effect associated with increased density of pneumococcal carriage in the nose and uncontrolled inflammatory immunological responses. The interaction of influenza virus and pneumococcus has been known and well documented. Recent works have shown that the Live Attenuated Influenza Vaccine (LAIV) enhances pneumococcal carriage in murine models. These results highlighted the potential effect of mass immunization of children with LAIV on pneumococcal carriage. Increased carriage could lead to increased pneumococcal disease in LAIV-vaccinated individuals as well as increased bacterial transmission within the population. LAIV has been licensed for use in children since 2011 in Europe, and has been increasingly administered in children and adults in the USA. There is an urgent need for a clinical trial that will determine the effect of LAIV on pneumococcal carriage dynamics.

The investigators have developed a safe and reproducible experimental human pneumococcal carriage (EHPC) model. The investigators will use EHPC to define the effect of antecedent and concurrent LAIV on pneumococcal carriage acquisition, density and duration. The investigators will perform two double - blinded Randomised Controlled Trials (RCT) to compare LAIV with Quadrivalent Inactivated Influenza Vaccine (QIV). The investigators will compare clinical symptoms, pneumococcal carriage density and duration associated with both vaccines administered antecedent to or concurrently with EHPC inoculation. Changes in the nasopharyngeal microbiome, inflammatory responses in the nasal mucosal and lung cellular immunity associated with influenza virus and pneumococcus interaction will be investigated. This project may provide some reassurance regarding the impact of mass immunization with LAIV on carriage or, if carriage is increased, will provide knowledge of how a natural carriage episode might develop into pneumonia in susceptible subjects during pandemic influenza.

Eligibility Criteria:
Inclusion Criteria:

* have capacity to give informed consent
* aged 18-50 yrs - ages chosen to minimise the risk of pneumococcal infection
* speak fluent English- to ensure a comprehensive understanding of the research project and their proposed involvement, in order to minimise any communication issues to maximise participant safety.

Exclusion Criteria:

* currently involved in another study unless observational or in follow-up phase (non-interventional)
* received any influenza vaccine in the last 2 years