Bacterial and Viral Infections Scientific Developments

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Bacterial and Viral InfectionsScientific
Developments

• E. David G. McIntosh
• MBBS FRACP FAFPHM MPH PhD
• Senior Medical Adviser, Wyeth
• Honorary Clinical Senior Lecturer, Imperial
  College

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Overview

• Recent developments
• New vaccine technology
• New routes of immunisation
• Antibiotics, antivirals, antifungals
• Barriers to progress
• Overcoming the barriers

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What is the burden of infectious disease?

• Awareness
• Reporting
• Surveillance
• Microbiology
• Virology
• Molecular biology
• Publication
• Vaccine probe

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Pneumococcal conjunctivitis

• 698 (13.8) of 5060 students at Dartmouth
  College, New Hampshire
• PFGE, DNA probe and multilocus sequence typing
• 56 item questionnaire on College web-site
• Subjects recruited to carriage study on web-site
• Prevention message emails

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What is driving developments?

• Scientific and medical discoveries?
• Computers and the internet?
• International travel? SARS
• Demands for absolute safety?
• Demands for absolute efficacy?

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Conjugate bacterial vaccines

• Basic principles of successfully immunising
  infants and young children and conferring
  immunological memory
• Haemophilus influenzae type b current catch-up
• Meningococcal C huge success in the UK
• Pneumococcal conjugate vaccine huge success in
  USA
• Donor immunisation enhances early antibody
  responses in patients undergoing haematopoietic
  cell transplantation
• StaphVAX (Nabi) serotypes 5 and 8 conjugate
  vaccine safe, immunogenic and conferred partial
  protection for 40 weeks against bactaeremia in
  end-stage renal disease

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Meningococcal B reverse vaccinology

• Complete sequence published in 2000
• Reverse vaccinology
• PCR amplification and cloning of selected open
  reading frames
• Expression, purification, use as vaccines in mice
• Immune sera tested in bactericidal assays

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OMV meningococcal B vaccine

• Clinical phase II trials of hexavalent
  meningococcal outer membrane vesicle vaccine from
  Netherlands National Institute of Public Hlth and
  the Environment (RIVM)
• Immunogenic in children 2 to 3 and 7 to 8 years
  of age

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HIV prime-boost

• Replicon-deficient vaccinia virus (MVA)
  expressing type 1 HIV 89.6 envelope (env) and
  simian-human hybrid virus (SIV) gagpol has been
  used to vaccinate rhesus macaques
• Induction of antibodies significantly enhanced by
  boosting with protein
• Level of viraemia after challenge was
  significantly lower in vaccinated animals versus
  controls
• Different experiment macaques first immunised
  with DNA and then boosted with recombinant MVA 24
  weeks later
• Good infection control

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DNA vaccines

• Injection of engineered DNA sequences from
  infectious organisms
• Carrier genome such as poxvirus or alphavirus
• Limited replication
• Production of protein
• Immune response

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New antibiotics the need

• No new classes of antibiotics in the 37 year
  period between nalidixic acid in 1962 and
  linezolid 2000
• Now, because of tighter regulatory requirements,
  fewer and fewer companies are investing in
  antibiotic development used to be within 15
  equivalence, now 10
• Increasing antibiotic resistance

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New antibiotics developments

• Screening potential targets for enzyme inhibitors
  that block vital metabolic pathways eg
  efflux-pump inhibitors and quorum-sensing
  signalling
• No new antibiotics in development based on genome
  sequencing, bioinformatics, combinatorial
  chemistry or high-throughput screening
• Targeting non-multiplying bacteria need to
  examine the molecular basis of tolerance of
  latent bacteria to antimicrobial agents

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Antiviral drugs

• Antiherpesvirus drugs
• Increasing resistance to nucleoside analogues
• Now targeting attachment, entry, gene expression,
  DNA replication, virion assembly and egress
• Latency the holy grail of antiherpesvirus drugs

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Antifungal drugs

• Increasing number immunocompromised patients
• Emerging fungal pathogens more difficult to treat
  with conventional therapies
• A number of new drugs BUT studied mainly in
  vitro, limited animal and human studies, need for
  established standards, pharmacokinetics,
  interactions and toxicities
• Often used with colony-stimulating factors or
  granulocyte transfusions many variables

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Summary - antibiotics

• Main barriers to development of new antibiotics
  are the regulatory environment, huge costs and
  the problem of non-multiplying bacteria
• Overcoming the barriers involves basic research
  into bacterial latency/dormancy, guaranteeing the
  pharmaceutical industry a return on antibiotic
  development and reviewing the regulatory
  environment

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Summary - vaccines

• Main barriers to deployment of vaccines are
  shortage of trained personnel to conduct vaccine
  trials, little reliance on the vaccine probe
  approach, sections of the media
• Overcoming the barriers involves the training of
  scientists towards vaccinology, molecular
  epidemiology, more reliance on the ability of
  vaccines to define burden and more reliance on
  prevention rather than cure