Interpandemic VaccinationInterpandemic VaccinationControversy, Challenge, Controversy, Challenge, OpportunityOpportunity

Robert W Malone, MD, MSRobert W Malone, MD, MS

RWMaloneMD@gmail.comRWMaloneMD@gmail.com

Overview: Overview: Interpandemic vaccines, a potential Interpandemic vaccines, a potential business opportunity?business opportunity?

• Introduction: Interpandemic vaccination, a metaphor Introduction: Interpandemic vaccination, a metaphor for a new approach to vaccine development.for a new approach to vaccine development.

• Context: Is this the right time for serious Context: Is this the right time for serious consideration of this issue?consideration of this issue?

• Feasibility: Are Interpandemic vaccines technically Feasibility: Are Interpandemic vaccines technically possible, would they be useful, and could they be possible, would they be useful, and could they be viable as product candidates?viable as product candidates?

• Strategy: Is “pandemic” influenza the right target, or Strategy: Is “pandemic” influenza the right target, or are there others?are there others?

• Conclusion: Possible action items.Conclusion: Possible action items.

Interpandemic vaccination, a metaphor Interpandemic vaccination, a metaphor for a new approach to vaccine for a new approach to vaccine development.development.

• Current metaphor: Vaccine products are Current metaphor: Vaccine products are designed to provide protection against designed to provide protection against disease caused by currently circulating disease caused by currently circulating pathogens and toxinspathogens and toxins

• Interpandemic metaphor: Develop, license, Interpandemic metaphor: Develop, license, and implement vaccine products designed to and implement vaccine products designed to provide protection from potential threat provide protection from potential threat agents (pathogens, toxins, other antigenic agents (pathogens, toxins, other antigenic biologically active substances)biologically active substances)

Interpandemic vaccination, a metaphorInterpandemic vaccination, a metaphor

• Current vaccine metaphor:Current vaccine metaphor:– Protection from disease caused by virus, bacteria, Protection from disease caused by virus, bacteria,

or toxin known to represent a significant current or toxin known to represent a significant current public health threat (typically with a well defined public health threat (typically with a well defined cost-benefit ratio)cost-benefit ratio)

– Protection from disease caused by an emerging or Protection from disease caused by an emerging or predictable threat with known biological propertiespredictable threat with known biological properties

• Influenza: WHO defined seasonal influenza strainsInfluenza: WHO defined seasonal influenza strains• Biodefense: Weaponized versions of natural pathogensBiodefense: Weaponized versions of natural pathogens

Interpandemic vaccination, a metaphorInterpandemic vaccination, a metaphor

• ““Interpandemic” metaphor:Interpandemic” metaphor:– Protection from disease caused by a potential but Protection from disease caused by a potential but

not yet circulating biologically active agent.not yet circulating biologically active agent.• Potential pandemic influenzaPotential pandemic influenza• Engineered biowarfare/bioterror threatsEngineered biowarfare/bioterror threats

– A proactive approach to public health in which A proactive approach to public health in which “herd immunity” may be used to reduce risk of “herd immunity” may be used to reduce risk of emerging pathogens.emerging pathogens.

• Constrain evolutionary options available to existing Constrain evolutionary options available to existing pathogenspathogens

• Anticipate and mitigate risks of engineered threat agentsAnticipate and mitigate risks of engineered threat agents• Complement “chinks in the armor” of existing innate and Complement “chinks in the armor” of existing innate and

adaptive immune systemadaptive immune system

– Associated with unique regulatory affairs “strategic Associated with unique regulatory affairs “strategic challenges”challenges”

Context: Is this the right time ?Context: Is this the right time ?

• Pandemic influenza planning and preparationPandemic influenza planning and preparation– Traditional approach inadequateTraditional approach inadequate

• Mismatch between epidemiologic modeling and Mismatch between epidemiologic modeling and manufacturing/distribution timelinesmanufacturing/distribution timelines

– Scientific knowledge has advancedScientific knowledge has advanced• Molecular virology studies are successfully identifying Molecular virology studies are successfully identifying

specific determinants of influenza A infectivity and specific determinants of influenza A infectivity and pathogenesispathogenesis

– Market existsMarket exists• Multiple governments are purchasing and stockpiling Multiple governments are purchasing and stockpiling

vaccine products in anticipation of a pandemicvaccine products in anticipation of a pandemic

– Regulatory pathways for licensure have been Regulatory pathways for licensure have been (partially?) created(partially?) created

Context: Is this the right time?Context: Is this the right time?

• Biodefense:Biodefense:– Current focus is on known (existing) threat agentsCurrent focus is on known (existing) threat agents– Near-future focus will be on potential engineered Near-future focus will be on potential engineered

pathogenspathogens– Forward-looking programs (DoD DTRA/JPO-Bio) Forward-looking programs (DoD DTRA/JPO-Bio)

are identifying biologic mechanisms and pathways are identifying biologic mechanisms and pathways which may be exploited to create threat agents which may be exploited to create threat agents (“chinks in the armor”)(“chinks in the armor”)

– A variety of funding programs are available to A variety of funding programs are available to support product developmentsupport product development

– Novel regulatory solutions for licensure have been Novel regulatory solutions for licensure have been created (“correlates of protection, animal rule”)created (“correlates of protection, animal rule”)

Feasibility: Interpandemic vaccinesFeasibility: Interpandemic vaccines

All are requiredfor feasibility

Feasibility: Technical considerationsFeasibility: Technical considerations(a “reality test” checklist)(a “reality test” checklist)

• Is there a need?Is there a need?• Is there a market?Is there a market?• Is there sufficient capital?Is there sufficient capital?• Can we identify appropriate target antigens?Can we identify appropriate target antigens?• Can we develop vaccine candidates directed against Can we develop vaccine candidates directed against

identified antigens?identified antigens?• Can we demonstrate pre-clinical POC ?Can we demonstrate pre-clinical POC ?• Can we perform non-clinical pharm/tox?Can we perform non-clinical pharm/tox?• Can we identify correlates of protection?Can we identify correlates of protection?• Can we assess clinical activity?Can we assess clinical activity?• Can we assess clinical safety?Can we assess clinical safety?

All are required for feasibility!

Feasibility: Technical Feasibility: Technical considerationsconsiderations

• Relevant technologies include:Relevant technologies include:– Molecular modelingMolecular modeling– Genetic drift analysis/phylogenetic modelingGenetic drift analysis/phylogenetic modeling– ““Synthetic” viruses (reverse genetics, reassortants)Synthetic” viruses (reverse genetics, reassortants)– Nucleic acid vaccinationNucleic acid vaccination– Engineered VLPEngineered VLP– Peptide vaccines (T and B epitope)Peptide vaccines (T and B epitope)– Novel protein antigen production (Baculovirus etc.)Novel protein antigen production (Baculovirus etc.)– Animal model systems (ferret, mouse, chimeric, adoptive Animal model systems (ferret, mouse, chimeric, adoptive

transfer)transfer)– Methods for assessing immunologic correlates (microneuts to Methods for assessing immunologic correlates (microneuts to

tetramers)tetramers)

• Not all vaccine systems may be appropriateNot all vaccine systems may be appropriate

Feasibility: Would an Interpandemic Feasibility: Would an Interpandemic vaccine be useful?vaccine be useful?

• The current influenza vaccine manufacturing The current influenza vaccine manufacturing model may result in vaccine not being model may result in vaccine not being available until after the majority of humans available until after the majority of humans have been infected. (+)have been infected. (+)

• One explanation for the reduced mortality in One explanation for the reduced mortality in older cohorts during 1918 epidemic is the older cohorts during 1918 epidemic is the earlier circulation of a related strain. (+)earlier circulation of a related strain. (+)

• It is possible that pre-existing titers against a It is possible that pre-existing titers against a related (slightly mis-matched) strain may related (slightly mis-matched) strain may reduce potency of strain-matched vaccine. (-)reduce potency of strain-matched vaccine. (-)

• Prior examples of seasonal vaccine strain Prior examples of seasonal vaccine strain “mismatch” suggest limited efficacy. (-)“mismatch” suggest limited efficacy. (-)

Feasibility: Would an Interpandemic Feasibility: Would an Interpandemic vaccine be commercially viable?vaccine be commercially viable?

• Currently in US, influenza vaccine is priced Currently in US, influenza vaccine is priced as a commodityas a commodity

• Various approaches currently being explored Various approaches currently being explored to differentiate products (Flumist, tetravalent- to differentiate products (Flumist, tetravalent- 2 A strains/2 B strains, filled syringe)2 A strains/2 B strains, filled syringe)

• Inclusion of pre-pandemic antigens in a Inclusion of pre-pandemic antigens in a multivalent seasonal vaccine could be multivalent seasonal vaccine could be consideredconsidered

• US DoD could facilitateUS DoD could facilitate– Has supported influenza vaccine innovationHas supported influenza vaccine innovation– Administration to DoD personnel under IND could Administration to DoD personnel under IND could

yield robust safety database supporting licensureyield robust safety database supporting licensure

Strategy: Is “pandemic” influenza the right Strategy: Is “pandemic” influenza the right target, or are there others?target, or are there others?

• Pandemic influenza:Pandemic influenza:– Unique current global consensus supporting Unique current global consensus supporting

planning , countermeasure development and planning , countermeasure development and stockpiling.stockpiling.

– Emerging recognition and consensus that current Emerging recognition and consensus that current vaccine manufacturing and distribution processes vaccine manufacturing and distribution processes may not be adequate- even if there were sufficient may not be adequate- even if there were sufficient capacity!capacity!

– Generally high level of public and professional Generally high level of public and professional support for planning and stockpiling (contrast to support for planning and stockpiling (contrast to Smallpox vaccine)Smallpox vaccine)

• Biological threat agentsBiological threat agents– Support (and funding) within specialized Support (and funding) within specialized

communities, public warinesscommunities, public wariness

Conclusion: Possible action itemsConclusion: Possible action items• Is there enthusiasm/support for interpandemic Is there enthusiasm/support for interpandemic

vaccine product within governmental and NGO vaccine product within governmental and NGO stakeholdersstakeholders– HHS/BARDA/OEPHHS/BARDA/OEP– DoDDoD– WHOWHO

• Is there a pathway to licensure for an Is there a pathway to licensure for an interpandemic vaccine product?interpandemic vaccine product?– CBERCBER– EMEAEMEA

• Is there support within influenza thought leaders, Is there support within influenza thought leaders, and what are the objections (if any)?and what are the objections (if any)?

• Could existing market opportunities be enhanced Could existing market opportunities be enhanced by adding a interpandemic product?by adding a interpandemic product?

Thank you for your interest and attention!Thank you for your interest and attention!

Personal contact information:Personal contact information:

Robert Malone, MD, MSRobert Malone, MD, MS

771 Mitchell Road771 Mitchell Road

Jasper, GA 30143Jasper, GA 30143

Maryland physician license #DOO55466Maryland physician license #DOO55466

Office 770 735 1549Office 770 735 1549

Cell 240 994 3334Cell 240 994 3334

Email Email RWMaloneMD@gmail.com

Website Website www.cieloazure.com