Exploring Novel Mechanisms of Vaccine Failure LAIV Pilot Study
Condition: Acquired Immune Deficiency Syndrome Virus
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Immunologic Deficiency Syndromes
Study type: Interventional
Phase: Phase 2

Summary: 
      Influenza ('flu) can cause severe infections, especially in people with weakened immune
      systems such as those with HIV. For this reason, yearly vaccination is recommended with the
      standard 'inactivated' influenza vaccine to try and prevent infections in these populations.
      It is also recommended in all health care workers, to help prevent the spread of influenza
      within healthcare settings. However, having HIV infection may mean vaccines work less well in
      some people and the investigators do not completely understand why. An alternative to the
      standard 'inactivated' annual influenza vaccine is the 'live attenuated influenza vaccine'
      (LAIV), which means it consists of weakened versions of the influenza virus.

      Unlike the standard vaccine, which is given by injection, LAIV is a spray that is given into
      each nostril. It is now given to children in the UK in preference to the standard vaccine as
      it results in greater protection from influenza. In some other countries, like the USA,
      adults are also given LAIV, where it seems to work just as well as the standard vaccine. A
      few studies in the past have shown that LAIV is safe and effective in HIVinfected children
      and adults. The investigators want to give LAIV to HIVinfected and HIV negative individuals,
      to try to find out new information about how HIV infection may change the way in which people
      respond to vaccines. The investigators will do this by comparing both the early genetic
      response to the vaccines and later responses from cells specifically targeted to fight
      influenza ('Tcells'), in these groups. In the long term, the investigators hope that this
      will lead to designing new ways of improving the response to vaccines in HIVinfected people.
      As LAIV is given into each nostril, rather than an injection, the investigators also want to
      see if LAIV results in Tcells in the lung that are specifically targeted to fight influenza
    

Detailed description: 
      The emerging field of systems vaccinology offers an unbiased, global approach to studying
      immune responses to vaccines, unlike the traditional reductionist approaches that focus on
      specific arms of the immune system (1,2).

      Recent work has studied responses to the trivalent inactivated influenza vaccine (TIV) and
      intranasal live attenuated influenza vaccine (LAIV) in immunocompetent adults, showing
      contrasting early transcriptional signatures elicited by the two vaccines (3). LAIV induces
      type I interferon related genes, antigen presenting cells (3) and mucosal IgA (4), suggesting
      that protection may be conferred via mucosal immunity and Tcells primed by early innate
      responses (5,6), rather than the TIV induced systemic antibody response. This approach has
      revealed novel insights into how early molecular signatures (e.g. expression of
      Calcium/calmodulin dependent kinase IV) correlates with later humoral immune responses, but
      similar relationships between innate and Tcell responses in response to LAIV remain
      unexplored3.

      Influenza is a common respiratory viral infection in HIV infected individuals worldwide, who
      are at a greater risk of severe infection even in the antiretroviral therapy (ART) era (7,8).
      Although immunization with TIV reduces these risks, as with other vaccines in HIVinfected
      individuals (9,10), TIV is poorly immunogenic in the immunosuppressed and new strategies are
      required to optimise protective immunity (1114). A systems vaccinology approach comparing the
      effects of LAIV in HIV infected and uninfected adults could reveal novel mechanisms of
      vaccine failure in those with suboptimal vaccine responses and in turn lead to potential ways
      of subverting this immune defect (2).

      LAIV is licensed for use in healthy children and adults aged 2 - 49 years in the United
      States of America. It has also been introduced for vaccination of children in the UK in 2013
      onwards, with a license for use in children and adolescents aged 24 months to 18 years of age
      (including those with asymptomatic HIV infection). Although initial concerns existed about
      the safety of LAIV in HIV infected individuals, several studies in both children and adults
      have not demonstrated any significant adverse effects (1518). A large study that administered
      either LAIV (n = 122) or TIV (n = 121) to HIV infected children (mean age 12) found the
      safety profile of the two vaccines to be similar (including incidence of pulmonary symptoms),
      other than an increased incidence of injection site reactions in the TIV arm (17).

      No effect on CD4 count or viral load was observed. Approximately 23% of children were found
      to shed vaccine strains of influenza within the first week following vaccination, which is
      similar to rates in HIV negative children. A study of HIV infected (n = 57) and uninfected (n
      = 54) adults also reported a similar safety profile, with rates of reactogenicity following
      LAIV equivalent between the two groups, but also no different to placebo arms, other than an
      increase in mild self limiting rhinorrhea and nasal congestion in the LAIV arms (16).
      Interestingly, in contrast to studies in children, only one adult was found to shed vaccine
      influenza strains, which is likely due to the attenuated nature of LAIV and preexisting
      antiinfluenza immunity in adults. While traditionally HIV infection is a relative
      contraindication to live vaccine administration, there is also now good experience with
      safely using live vaccines such as the Yellow Fever vaccine in subjects with CD4 counts
      >200/mm3 (19) and is included in travel vaccination guidance for HIV infected individuals who
      meet these criteria (20). Recent guidance on immunisation of immunocompromised adults also
      recommends the use of live varicella vaccine in HIV infected adults who are not severely
      immunocompromised and are nonimmune to varicella (20). As live vaccines typically induce a
      more potent immune response than inactivated or subunit vaccines, this approach warrants
      further investigation in HIV infected subjects. While LAIV is more immunogenic than TIV in
      children (21,22), data suggests that LAIV and TIV have similar effectiveness in preventing
      influenza in healthy adults, despite lower antibody seroconversionin LAIV (23,24). LAIV is
      more likely to confer protection via innate immune priming of mucosal cellular responses
      (3,23,24). In addition, LAIV may provide protection against mismatched strains of influenza
      (21,22) and unlike TIV, result in protective immunity that extends beyond the year of
      administration (25).

      The importance of Tcell responses in reducing the severity of influenza is increasingly
      recognised (26) and may be a better correlate of protection than antibodies in the elderly
      (2729). Murine data have demonstrated the role of LAIV elicited pulmonary influenza specific
      CD8+ Tcells, in providing longlived protection against subsequent viral challenge (3032),
      although this is yet to be confirmed in human studies. This protection appears to extend to
      heterologous viruses, as the Tcell response is directed primarily at internal proteins, which
      are conserved across many strains. This is important, given the ongoing threat of new
      emerging influenza viruses.

      HIV infected subjects have impaired naturally acquired influenza specific Tcell responses in
      both blood and lung (33,34). No human studies exist on the degree of pulmonary Tcell immunity
      induced by LAIV in HIV infected or immunocompetent adults. No studies have also used a
      systems biology approach to study the immune response to live vaccine challenge in
      HIVinfection. While HIVinfected subjects may display an aberrant systemic immune response to
      LAIV, it could also provide a useful strategy to induce potent heterotypic mucosal immunity
      in a population who display suboptimal responses to TIV. The study will be conducted in
      compliance with the protocol, Good Clinical Practice (GCP) and the applicable NHS R&D Form
      IRAS Version 3.5 8 155866/618731/14/528 many strains. This is important, given the ongoing
      threat of new emerging influenza viruses.

      HIV infected subjects have impaired naturally acquired influenza specific Tcell responses in
      both blood and lung (33,34). No human studies exist on the degree of pulmonary Tcell immunity
      induced by LAIV in HIV infected or immunocompetent adults. No studies have also used a
      systems biology approach to study the immune response to live vaccine challenge in HIV
      infection. While HIV infected subjects may display an aberrant systemic immune response to
      LAIV, it could also provide a useful strategy to induce potent heterotypic mucosal immunity
      in a population who display suboptimal responses to TIV. The study will be conducted in
      compliance with the protocol, Good Clinical Practice (GCP) and the applicable regulatory
      requirements.
    

Intervention name(s): Live attenuated Vaccine- Fluenz Tretra
Intervention type(s): Biological
Intervention description(s): Intra-nasal administration of 0.2ml (0.1ml in each nostril).
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science