The Effect of Live Attenuated Inactivated Influenza Vaccine on Experimental Human Pneumococcal Carriage Study
Condition: Pneumonia; Influenza, Human
MeSH terms: Influenza, Human; Pneumonia
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Study one: LAIV + Inoculation; Study one: Placebo + Inoculation; Study two: Inoculation + LAIV; Study two: Inoculation + placebo
Intervention type(s): Biological; Biological; Biological; Biological
Intervention description(s): Pneumococci bacteria nasal inoculation following vaccination with LAIV and intramuscular placebo; Pneumococci bacteria nasal inoculation following vaccination QIV with nasal placebo spray; Pneumococci bacteria nasal inoculation prior to vaccination with LAIV and intramuscular placebo; Pneumococci bacteria nasal inoculation prior to vaccination QIV with nasal placebo
Other intervention name(s): FLUMIST or FLUENZ AstraZeneca; Fluarix Tetra GlaxoSmithKline; FLUMIST or FLUENZ AstraZeneca; Fluarix Tetra GlaxoSmithKline
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: DBRCT performed as two studies over two flu seasons. 2 arms to each study.
Masking: Double (Participant, Investigator)
Primary purpose: Health Services Research
Keywords: Human challenge models; Immunity; Streptococcus pneumoniae; Live Attenuated Influenza Vaccine