Emerging And Re Emerging Infectious Disease Vaccines 09 Dec08 Final

Emerging and Re-emerging
Infectious Diseases:
New Vaccine Product Opportunities

Emerging and Re-Emerging Infectious
Diseases:
• Who defines an emerging or re-emerging infectious disease?
• What pathogens are we talking about?
• Where are diseases emerging or re-emerging?
• Why are diseases emerging or re-emerging?
• How can we identify and analyze new vaccine markets associated
with these diseases?
• Where can we get capital to develop vaccines for these pathogens?
• Are there overlooked vaccine product opportunities?
• Can we overcome the development clinical and regulatory
challenges?

Emerging and Re-Emerging Infectious Diseases
Who defines an emerging or re-emerging
infectious disease?

• National Institutes of Allergy and Infectious
Disease, NIH
– Emerging Infectious Diseases:
• previously unknown diseases or known diseases
whose incidence in humans has significantly increased
in the past two decades
– Re-Emerging Infectious Diseases:
• known diseases that have reappeared after a
significant decline in incidence

What pathogens are we talking about?

• Group I—Pathogens Newly Recognized in the Past Two
Decades
• Group II—Re-emerging Pathogens
• Group III—Agents with Bioterrorism Potential
– NIAID—Category A
– NIAID—Category B
– NIAID—Category C

• Group I—Pathogens Newly Recognized in the Past Two
Decades
• •
Acanthamebiasis Helicobacter pylori
• •
Australian bat lyssavirus Hendra or equine morbilli virus
• •
Babesia, atypical Hepatitis C
• •
Bartonella henselae Hepatitis E
• •
Ehrlichiosis Human herpesvirus 8
• •
Encephalitozoon cuniculi Human herpesvirus 6
• •
Encephalitozoon hellem Lyme borreliosis
• •
Enterocytozoon bieneusi Parvovirus B19


• Group II—Re-emerging Pathogens
– Enterovirus 71
– Clostridium difficile
– Mumps virus
– Streptococcus, Group A
– Staphylococcus aureus

• NIAID Category A
• Bacillus anthracis (anthrax) • Viral hemorrhagic fevers
– Arenaviruses (LCM, Junin
• Clostridium botulinum toxin
virus, Machupo virus,
(botulism)
Guanarito virus, Lassa Fever)
• Yersinia pestis (plague)
– Bunyaviruses (Hantaviruses,
• Variola major (smallpox) and Rift Valley Fever)
other related pox viruses – Flaviruses (Dengue)
• Francisella tularensis – Filoviruses (Ebola, Marburg)
(tularemia)

• Food- and waterborne
• NIAID Category B
pathogens
• Burkholderia pseudomallei
– Bacteria
• Coxiella burnetii (Q fever) • Diarrheagenic E.coli, Pathogenic
Vibrios, Shigella species, Salmonella,
• Brucella species (brucellosis) Listeria monocytogenes, Campylobacter
jejuni, Yersinia enterocolitica
• Burkholderia mallei (glanders) – Viruses
• Chlamydia psittaci • Caliciviruses, Hepatitis A
– Protozoa
(Psittacosis)
• Cryptosporidium parvum, Cyclospora
• Ricin toxin (from Ricinus cayatanensis, Giardia lamblia,
Entamoeba histolytica, Toxoplasma
communis)
– Fungi
• Epsilon toxin of Clostridium • Microsporidia
perfringens • Additional viral encephalitides
• –
Staphylococcus enterotoxin B West Nile virus, LaCrosse, California
encephalitis, VEE, EEE. WEE.
• Typhus fever (Rickettsia Japanese Encephalitis virus, Kyasanur
Forest virus
prowazekii)

• NIAID Category C, Emerging infectious diseases
• Tick-borne hemorrhagic fever • Rabies
viruses (Crimean-Congo • Prions
Hemorrhagic Fever virus)
• Chikungunya virus
• Tick-borne encephalitis viruses
• Severe acute respiratory
• Yellow fever syndrome-associated
• Multidrug-resistant TB coronavirus (SARS-CoV)
• • Coccidioides immitis
Influenza
• • Coccidioides posadasii
Other Rickettsias

Where are diseases emerging or re-emerging?

Where are diseases emerging or re-emerging?
• Latin America
– Dengue, Yellow fever, Meningococcal meningitis outbreaks increasingly
common
– See http://www.paho.org/English/ad/dpc/cd/eid-eer-ew.htm for PAHO
reports of emerging and re-emerging infectious disease reports
• SE Asia
– (WHO analysis) Avian influenza, measles, infectious hepatitus, Nipah virus,
Meningococcal disease, Malaria, Tetanus, Scrub typhus, Dengue, Cholera,
Mumps, Japanese Encephalitis, Poliomyelitis, Leptospirosis, Typhoid Fever
– http://www.searo.who.int/LinkFiles/Publication_139-combating-emerging.pdf
• China
– Very challenging to obtain accurate epidemiologic information
• Africa
– Surveillance is in its infancy
– HIV, Tuberculosis (incl MDR), Streptococcus pneumoniae, Haemophilus
influenzae, Neisseria meningitidis, Staphylococcus aureus (incl MRSA),
Enterococcus, Shigella dysenteriae, Viral Hemorrhagic Fevers, Schistosoma

Why are diseases emerging or re-emerging?
• Human social and behavioral changes
– Travel with expanded distance, speed, ecological diversity
– Demographic changes
– Land use, habitat encroachment (rainforest, wetlands)
– Use of antibiotics and pesticides
– Host switching, exposure to pathogen reservoirs (animal, arthropod)
• Consumption of Civet cat meat (SARS-CoV), Gambian rats as pets (monkeypox),
Spreading of Aedes aegypti mosquito (Dengue/Yellow fever )
• Environmental changes
– Global warming, changes in weather and precipitation patterns
– Increased population density facilitates transmission, pathogen evolution
• Technological changes
– Research advances reveal new infectious disease basis for pathobiology
• Helicobacter (ulcers)
– New diagnostic technology and/or public health surveillance detecting new
pathogens
• Norovirus (diarrheal disease), Coronavirus (SARS-CoV)

How can we identify and analyze new vaccine
markets associated with these diseases?
• Challenges in market analysis
– How to define incidence and prevalence?
– How to assess acceptable price per dose, and for which markets?
– Can separate markets be defined or stratified at present or future
• travelers vaccines, military purchasers, WHO/UNESCO
• developed, emerging, third world economies and governments
– What are the impacts and opportunities associated with government and
NGO/non-profit actors on markets?
• Opportunities with Emerging and Re-Emerging ID markets
– Markets are often ―under the radar‖
• Large and well capitalized biopharma invests in well defined markets
• Window of opportunity for flexible product development teams
– Significant non-dilutive capital available to support product development
– Stockpile or special markets (DoD) may be available
• DoD/Stockpile purchases may be associated with easier target populations (healthy
adults)

How can we identify and analyze new markets?
– Monitor formal surveillance networks
• DoD Global Emerging Infections Surveillance and Response System (DoD-
GEIS)
– http://www.geis.fhp.osd.mil/
• Training in Epidemiology and Public Health Intervention Network (TEPHINET- 32
countries)
– http://www.tephinet.org/
• WHO Collaborative Centers Network for Global Surveillance of Communicable
Diseases currently in development
– http://www.who.int/immunization_monitoring/en/
• US Centers for Disease Control and Prevention, UK Public Health Laboratory
Service, the French Pasteur Institutes all maintain global and regional
surveillance data
– Consultations with in-country infectious disease and epidemiology thought
leaders
– Survey country-specific pricing structures for existing vaccines
– Monitor acquisition and project strategies of forward-looking global and
regional stakeholders
• US DoD, NIAID, CDC, WHO, Bill and Melinda Gates Foundation, GAVI

GAVI (Global Alliance for Vaccines and Immunization) annual process
– Step 1: Diagnostic
• Gather relevant information to profile each disease/vaccine under consideration
• Consider the types of associated activities that could be funded to ensure successful vaccine
• introduction (February-March)
– Step 2: Consultations
• Carry out 7 in-country consultations along with online, video and phone consultations to
solicit input from key stakeholders.
• Most recent full consultation report of country input is available on the website
(http://www.gavialliance.org/resources/Stakeholder_consultation_report_Jun08.pdf)
– Step 3: Synthesis and Vaccine Evaluation
• Identify a range of scenarios (vaccine portfolio themes) associated with packages of multiple
vaccines over different timeframes.
– Step 4: Strategy Development and Investment Requirements
• Present recommended vaccine investment theme to the GAVI Alliance Board
• Define investment envelope along with long-term income projections
• Prepare implementation plan considering the specific financial implications (and
corresponding fundraising strategy) as well as the associated activities and timeframe for
investments.
http://www.gavialliance.org/resources/3____Vaccine_Investment_Strategy.pdf

• WHO priority list defines global consensus for proven vaccine
preventable diseases
– Based on 10 criteria ranked by relative importance
• mortality; epidemic/pandemic potential; economic impact; case fatality rate;
disease incidence in the highest burden regions; long term sequelae; morbidity;
inequity; lack of other alternative treatment or prevention measures; and severity
of symptoms.
– 18 diseases clustered into three groups
• quot;Very High Priority― (Malaria and Pneumococcal Disease)
• quot; High Priorityquot; (Cervical Cancer (HPV), Cholera, Dengue, Japanese
Encephalitis, Meningococcal ACWY, Rabies, Rotavirus, Seasonal influenza,
Typhoid Fever, and Yellow Fever)
• quot; Medium Priorityquot; (Hepatitis A, Hepatitis E, Meningococcal B, Mumps, Rubella,
and Varicella).
– Additional emphasis on injectable polio vaccine (IPV) for GAVI
countries (currently insufficient global supply capacity to meet projected
need)


• WHO priority list defines global consensus for proven vaccine
preventable diseases (continued)
– Organizations managing global vaccine acquisition
• UNICEF (http://www.unicef.org/supply/index_immunization.html )
• PAHO (http://www.paho.org/english/hvp/hvi/revol_fund.htm )
– List of United Nations Prequalified Vaccines and vaccine priorities is
updated annually
• http://www.who.int/immunization_standards/vaccine_quality/pq_suppliers/en/
– Standardized process for petitioning for WHO prequalification status
• Requires submission of product summary file (PSF)
• http://www.who.int/vaccines-documents/DocsPDF07/870.pdf

Where can we get (non-dilutive) capital to develop
vaccines for these pathogens?
• NIH- NIAID
– http://www3.niaid.nih.gov/topics/emerging/default.htm
• US Department of Defense (US Army Medical Research & Materiel
Command)
– http://www.usamraa.army.mil/pages/Baa_Paa/baa_choice.cfm
• DARPA
– http://www.darpa.mil/dso/thrusts/bwd/act/rva/index.htm
• Bill and Melinda Gates Foundation
– http://www.gatesfoundation.org/grantseeker/Pages/overview.aspx
• Wellcome Trust
– http://www.wellcome.ac.uk/funding/
• PATH
– http://www.path.org/
– http://www.path.org/vaccineresources/index.php

Are there overlooked vaccine product opportunities?
• Case study #1 Burkholderia pseudomallei (Melioidosis) ―The great
mimicker‖- with no clear vaccine candidate
– Gram negative bacterium (soil), infects when soil is disrupted
– Endemic in Thailand, Singapore, Malaysia, Burma, Northern Australia
– Reported in Southern China and Hong Kong, Brunei, Taiwan, India, and
Laos, and sporadic cases in Central and South America, the Middle East,
the Pacific, several African countries, and at least five cases in UK (likely
underreported)
– Often misdiagnosed as Tuberculosis (―Vietnamese Tuberculosis‖)
– In northeast Thailand, 80% of children are seropositive by the age of 4
– Relatively refractory to medical management
– Associated with increased rainfall (distribution likely impacted by global
climate change)
– Appears to require both humoral and cellular responses for control
– High priority for US Military vaccine development programs
– Genome comprised of two chromosomes is completely sequenced
• http://www.sanger.ac.uk/Info/Press/2004/040914.shtml

Are there overlooked vaccine product opportunities?
• Case study #2 Norovirus (one leading vaccine candidate- Ligocyte)
– RNA virus (Calciviridae, positive ssRNA genome)
– Causitive agent of 90% of worldwide epidemic (non-bacterial) gastroenteritis
– Common cause of epidemic outbreaks in closed environments (ships, geriatric
care, pediatric daycare centers)
– 12% of severe gastroenteritis cases among children <5 years of age and 12% of
mild and moderate diarrhea cases among persons of all ages.
– CDC estimates Norovirus infections cause 64,000 episodes of diarrhea requiring
hospitalization and 900,000 clinic visits among children in industrialized countries,
and up to 200,000 deaths of children <5 years of age in developing countries.
– Cannot be cultured on any known cellular substrate
– Incidence currently being defined (PCR stool analysis, diarrheal disease
incidence monitoring due to rotavirus vaccine)
– No reagents available to evaluate seroprevalence
– Genetic analysis indicates genetic drift to escape mutant development
approximately every two years
– No current surveillance outside of North America, EU
– High priority for US Military vaccine development programs

Development, Clinical and Regulatory challenges?
• Developmental challenges
– Basic Scientific background and context may not be readily available
• Protective antigens may need to be identified
• Role of innate and adaptive immune responses may need to be
characterized
• Identification of mechanisms of host immune response, pathobiology and
other mechanisms (or correlates) of protection may be necessary
– Practical pre-clinical testing infrastructure is required
• Conditions for propagation and standardization of research and challenge
strains may need to be developed
• Animal models of disease may need to be developed and validated
• Standardized animal challenge protocols must be developed
• Immunoassays and genetic analysis tools (PCR etc.) are required both to
define human epidemiology and to assess animal testing outcomes
• Novel vaccine (and adjuvant) technologies may require development of
novel toxicology assays

Development, Clinical and Regulatory challenges?
• Clinical challenges
– Defining the labeled indication
• Protection against infection or disease- if disease, how defined?
• What cohort(s) and target markets?
– Travelers or military personnel?
– All ages and risk groups or healthy adults at risk?
– Multi-step licensure?
– Defining efficacy endpoints (Phase 2)
• Requires understanding of immunology, pathobiology and other
mechanisms (or correlates) of protection
– Demonstrating field efficacy (Phase 3)
• Is the incidence high enough to warrant the investment?
• May require studies in regions which may lack necessary clinical trial
experience
• Efficacy power calculations (study cohort size) require accurate estimates
of incidence and prevalence

Development, clinical and regulatory challenges?
• Regulatory challenges
– What countries competent regulatory authorities will support
licensure?
– International bioethical concerns may create barriers and
complications to licensure
– Will EMEA/CBER pathways for licensure of vaccines for non-EU/US
markets be employed?
– Correlates of protection are undefined (and may be undefinable)
– Risk/benefit ratio may be difficult to define or may change over time
– What strategic pathway will be employed to enable WHO selection
and UNICEF/PAHO purchase (if this is intended)
– Complexities and timelines for competent authorities in emerging
economies may create significant barriers to time and cost-effective
licensure
– Application of animal rule (CBER) may be problematic

Emerging and Re-emerging
Infectious Diseases:
Robert W Malone, MD, MS
http://www.rwmalonemd.com

• Question and answer session
• Thanks for participating!
• If you wish a copy of this presentation with the
associated web links, please send an email
requesting a copy to the following address:
marketing@biopractice.com

Emerging And Re Emerging Infectious Disease Vaccines 09 Dec08 Final

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