Yellow Fever Vaccine on Statin/ Non Statin Subjects
Condition: Yellow Fever Vaccine; Yellow Fever
MeSH terms: Yellow Fever; Fever; Hyperthermia
Study type: Interventional
Phase: Phase 2

Summary: 
      Since the 1st pandemic of the 21st century caused by SARS coronavirus, the world has
      experienced outbreaks of swine origin H1N1 influenza, Ebola and Zika viruses, which have all
      resulted in global health crises. Rapid mass vaccination with an effective vaccine such as a
      live attenuated vaccine, of vulnerable immune-naïve populations to establish herd immunity is
      an approach to control outbreaks. Such live attenuated vaccine had been used with great
      success in sporadic yellow fever outbreaks and recently successfully employed in Ebola field
      trial, both of these diseases have the potential for pandemic spread. Indeed, live attenuated
      vaccines have proven especially effective in controlling childhood diseases and have even
      succeeded in eradicating polio and measles from most parts of the world. However, deployment
      of such vaccines for pandemic control cannot be limited to children but must include adults
      in order to rapidly elevate herd immunity rates to halt transmission. Vaccinating adults may
      produce efficacy rates significantly different to those observed in children due to the
      prevalence of chronic diseases and their associated metabolic complications. Presently, there
      are 1 billion people who are overweight, many suffer from concurrent metabolic disorders. As
      activation of the adaptive immunity is reliant on a robust innate immune response to
      vaccines, metabolic disorders and long-term anti-inflammatory therapy with interventions such
      as statins may reduce vaccine immunogenicity resulting in suboptimal efficacy in this
      subpopulation. This study would therefore test the hypothesis that statins reduce live
      attenuated vaccine immunogenicity. We will combine a clinical trial with systems vaccinology
      approaches to define the impact statins has on the innate immune, B and T-cell responses to
      live attenuated vaccination. Our study will thus extend upon another recently completed trial
      by us and will provide new insights into the determinants of vaccine efficacy in a rapidly
      growing and aging population globally
    

Detailed description: 
      Despite successful control of many infectious diseases since the 19th century, viral diseases
      remain an important and significant health burden in the 21st century. In fact, the turn of
      the 21st century saw the emergence of not only new but also re-emergent pathogens such as
      SARS, MERS, West Nile, Ebola, dengue and Zika viruses. In addition, the modern world is
      highly mobile and interconnected. The spread of infectious diseases is imminently only a
      flight away. It is thus of no surprise that epidemics in this century are happening at a much
      faster pace and spreading quicker to cause disruption to human health, society and the
      economy. Vaccination, particularly with a live attenuated vaccine (LAV), which has the most
      successful track record among the various forms of vaccines, remains the most economical
      public health tool available to prevent or stop the spread of infections and alleviate human
      sufferings. Rapid mass vaccination of at risk populations to establish herd immunity has been
      successfully employed to control sporadic YF outbreaks in Africa and South America. More
      recently, a clinical trial showed that ring vaccination of contacts with Ebola patients
      completely abrogated secondary virus spread. Vaccination in times of pandemics, however,
      cannot be limited to children but must include adults in order to rapidly elevate herd
      immunity rates to halt further transmission.

      The use of LAV in adults has several important challenges that have not been systematically
      addressed. The population demographics in Singapore, like most developed countries have
      changed drastically over the past 3 decades. Along with improved nutrition, populations are
      now living longer but with increasing prevalence of chronic diseases such as obesity and
      dyslipidemia. Consequently, the anti-cholesterol group of drugs, with pleiotropic properties,
      statins, are among the commonest drugs prescribed globally for the prevention of secondary
      cardiovascular and major vascular complications. There is presently a mounting concern that
      the anti-inflammatory and immune-modulatory effects of statins could have a detrimental
      effect on vaccine efficacy. Indeed, studies examining inactivated influenza vaccination in
      older individuals had observed lower immunogenicity and overall efficacy with statin use.
      Whether statins have a similar negative immunogenicity effect on LAV remains undefined. The
      anti-inflammatory effects may dampen innate immune responses critical for triggering adaptive
      immunity resulting in reduced immunogenicity. Conversely, the suppression of innate immune
      responses could favor LAV infection and replication, allowing adaptive immune cells a longer
      period to sense the antigen, become activated and differentiated for improved immune
      response.

      In this study, an experimental medicine investigation that leverages on a recently completed
      clinical trial that the PI led examining how cross-reactive antibodies altered the
      immunogenicity of yellow fever (YF) vaccination. We will seek to clarify the effects of
      statin on LAV immunogenicity. YF vaccine is an excellent LAV, which remains the WHO
      recommended response to the ever-present threat of YF outbreak. It has also served as an
      important model for studying human antiviral immunity. We propose to test the hypothesis that
      long term statins therapy alters YF LAV immunogenicity by coupling the power of a clinical
      trial with comprehensive systems vaccinology to define the impact statins have on the
      adaptive immune response to YF vaccination. This study will elucidate how statins modulate
      the networks that drive immunity to vaccination in a fast growing population globally.
      Knowledge on how statins impact LAV immunogenicity would inform public health authorities on
      the size of the general population that should be vaccinated to compensate for alterations in
      immunogenicity in this subpopulation to achieve sufficient herd immunity for epidemic and
      pandemic control.
    

Intervention name(s): Stamaril (live attenuated yellow fever vaccine)
Intervention type(s): Drug
Intervention description(s): They will receive a single dose of 0.5ml of Stamaril (live attenuated yellow fever vaccine)
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Health Services Research