title: The role of pre-existing cross-reactive antibodies in determining the efficacy of vaccination in humans: study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Epidemic viral diseases have become more prevalent.. Among the various strategies to prevent such epidemics, vaccination is the most cost-effective. However, populations that are immunized are typically already exposed to multiple previous vaccinations or natural infections. Studies from this and other laboratories have revealed that pre-existing dengue antibodies can either inhibit or enhance subsequent dengue infection depending on the pre-existing antibody levels. While cross-reactive antibody is potentially pathogenic in dengue, how it impacts immune response to vaccination is unclear. Aggregated at the site of vaccination and the respective draining lymph nodes are antigen-presenting and immune regulatory cells that express Fc receptors and play pivotal roles in determining the magnitude and polarity of the immune response. Vaccine uptake by these antigen-presenting cells may thus be either inhibited or enhanced when vaccines are opsonized with cross-reactive antibodies.
  
  
  METHODS
  In view of the limited knowledge on how cross-reactive antibodies affect vaccination outcome, we propose a study that exploits the known cross reactivity between Japanese encephalitis (JE) virus antibody and yellow fever (YF) vaccine. We hypothesize that cross-reactive antibodies impact antibody response to YF at the point vaccination in a concentration-dependent manner by altering both vaccine uptake and the innate immune response by antigen presenting cells. We will structure an open-label clinical trial on sequential vaccination with JE and YF vaccines, with different time intervals between vaccinations. This would test immune response to YF vaccination in subjects with different titer of cross-reactive JE vaccine-derived antibodies. The clinical materials obtained in the trial will drive basic laboratory investigations directed at elucidating how heterologous antibody affect vaccination at the molecular level. YF neutralizing antibody titer will be measured using plaque reduction neutralization test against the vaccine strain YF17D. Innate immune response will be characterized genetically using either microarray or digital PCR (or both). The innate immune response will also be characterized at the protein and metabolite level using Luminex bead technology and lipidomic/metabolomic approaches.
  
  
  CONCLUSIONS
  This proposed study represents one of the first to examine the role of cross-reactive antibodies in modulating immune responses to vaccines, the findings of which may re-shape vaccination strategy.
  
  
  BACKGROUND
  Clinical Trials.gov registration number: NCT01943305 (3 September 2013).
authors: Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore, Singapore, 169856. jenny.low@sgh.com.sg.
authors: Jenny G
authors: JG
authors: Low
authors: Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore, Singapore, 169856. limin.wijaya@sgh.com.sg.
authors: Limin
authors: L
authors: Wijaya
authors: Singhealth Investigational Medicine Unit, Singapore General Hospital, Outram Road, Singapore, Singapore, 169608. greg.li.k.y@singhealth.com.sg.
authors: Greg K Y
authors: GK
authors: Li
authors: Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore, Singapore, 169856. eleanor.lim@mohh.com.sg.
authors: Eleanor Y L
authors: EY
authors: Lim
authors: Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore, Singapore, 169856. koinlon.shum@mohh.com.sg.
authors: Aland K L
authors: AK
authors: Shum
authors: Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, 8 College Road, Singapore, Singapore, 169857. yinbun.cheung@duke-nus.edu.sg.
authors: Yin-Bun
authors: YB
authors: Cheung
authors: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore, Singapore, 169857. engeong.ooi@duke-nus.edu.sg.
authors: Eng-Eong
authors: EE
authors: Ooi
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology*; D002985:Clinical Protocols; D003429:Cross Reactions; D053059:Dengue Vaccines / Q000009:adverse effects / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D014611:Vaccination
chemical_list: D000914:Antibodies, Viral; D053059:Dengue Vaccines