The following is a text-only version of the notes from Dr. David Fedson's presentation at last week's First International Conference on Avian Influenza in Humans
Please see WHO CONSULATION FOR THE DEVELOPMENT OF A GLOBAL ACTION PLAN TO INCREASE THE SUPPLY OF PANDEMIC INFLUENZA VACCINES for an in-depth discussion of the problems of developing and distributing any effective H5N1 vaccination.
Asian European Conference on Avian Influenza 2006
Paris, 29-30 June 2006
Pandemic Influenza: A Potential Role for Statins in Treatment and Prophylaxis
David S. Fedson, MD
Prospects for Global Pandemic Vaccination: a WHO Assessment
?WHO is using international meetings to urge the international community to find ways to increase manufacturing capacity and ensure that developing countries have access to an effective vaccine at an affordable price. On current trends, however, most developing countries will have no access to a vaccine during the first wave of a pandemic and perhaps throughout its duration.?
--WHO, Global Programme on Influenza
Vaccine research and development, current status
November 2005
Six Interrelated Components of a Global Strategy for Pandemic Vaccination
Vaccine research and development
*Regulatory convergence
*Vaccine production capacity (GMP)
*IP issues and liability
*Vaccine purchasing, financing and distribution
*National vaccination programs
No institution or process exists or is planned that can do this at a global level!
Current Status of H5N1 Pandemic Vaccine Development
*Each company is developing its own H5N1 vaccine
*Government funding for clinical trials is limited, except for the US
*H5N1 vaccine viruses replicate poorly and are poorly immunogenic, even if adjuvanted
*In the event of an H5N1 pandemic, the global demand for vaccine will be >> 3-4 billion doses
Today, the world?s vaccine companies could produce enough doses of adjuvanted 30 mg HA vaccine in six months to vaccinate < 100 million people
Production capacity is unlikely to increase substantially within the next 3-5 years
Vaccination: the Likely Failure of a Top-down Response to a Pandemic
- Current efforts involve only a limited number of institutions, companies and governments, and only scientific, business and political elites are involved
- Management of the material and political logistics for global vaccination would require an elaborate international organization and be such a nightmare, it is not even being contemplated
*Pandemic vaccination will not be a realistic possibility for 85% of the world?s people who don?t live in countries with vaccine companies, and it will be difficult even for those who do
-
A Bottom-up Response to an Imminent Pandemic
*Elites have little or no control
*Uses large numbers of ordinary people in all countries
*Uses existing systems for delivering health care services to individuals as well as populations
*Uses existing resources that are affordable and already available worldwide
*Can be implemented on the first day of a pandemic
Statins: a Bottom-up Response to an Imminent Pandemic?
*Influenza increases AMIs, CHF and stroke
*Pro-inflammatory markers (CRP, TNF-a, IL-6) increase risk of CVD
*Influenza viruses up-regulate pro-inflammatory cytokines
*Influenza vaccination decreases AMIs, CHF and stroke
*Statins decrease CRP, TNF-a, and IL-6 and decrease risk of CVD
*Statins down-regulate pro-inflammatory cytokines
Statin-associated Protection in Syndromes with Cytokine Dysregulation
Author Study Statin Prev./Cont. Outcome Statin-assoc. reduction
Liappis (CID 2001) 388 cases continued bact-attr. mortality 87%
Almog (Circ 2004) 361 cases previous severe sepsis 87%
Kruger (ICM 2006) 438 cases continued bact-attr. mortality 92%
Hackam (Lancet 2006) 34,584/34,584 previous sepsis mortality 25%
Mancini (AJCC 2006) 4907/98,917 previous Hosp - COPD 26%
Protective Effect of Statins: Mortality from Bacteremia
*Retrospective study of 438 patients hospitalized with bacterial sepsis
*Conditional regression analysis to adjust for confounding variables
Bacteremia-attributable mortality
statin treated (6.1%) vs. not treated (18.3%)
OR = 0.29 (0.10 to 0.82)
continued Rx (1.8%) vs. no Rx (18.3%)
OR = 0.08 (0.01 to 0.60)
Kruger P et al. Intensive Care Med 2006; 32: 75-9.
Protective Effect of Statins: Population-based Study of Sepsis
*Ontario administrative database of patients discharged after hospitalization for acute cardiovascular disease
*Nested case-control study - 34,584 treated with statins and 34,584 propensity-matched untreated controls
Adjusted hazard ratios for statins (95% CIs)
All sepsis 0.81 (0.72 to 0.90)
Severe sepsis 0.83 (0.70 to 0.97)
Fatal sepsis 0.75 (0.61 to 0.93)
Hackam DG et al. Lancet 2006; 367: 413-8.
Protective Effect of Statins: Hospitalization for COPD in Quebec
Adjusted odds ratio
High-risk Low-risk
Treatment Myocard. revasc. NSAID Rx
cases/controls 946/18,774 4907/98,087
ACE inhibitors .87 .96
ARBs 1.04 .86
Statins .72 .74
Statins + ACEIs/ARBs .66 .77
Mancini GBJ et al. J Am Coll Card 2006; 47: 2554-60.
Statins and Pneumonia: An Epidemiological ?Signal of Protection?
*Population-based, nested case-control study of 1227 cases of pneumonia
*Three controls for each person on statins < 30 days
Adjusted OR (95% CI)
pneumonia hospitalization 0.63 (0.46 to 0.88)
30-day pneumonia mortality 0.47 (0.25 to 0.88)
Schlienger RG et al. Submitted for publication
Statins and Influenza-related Pneumonia: Reduction in 30-day Mortality
*8652 pneumonia patients ≥ 65 y.o. hospitalized October 1, 1998 - September 30, 1999
*Generalized linear mixed-effect model
Adjusted OR (95% CI)
Treatment (< 90d) Full year Flu season
Statins 0.62 (.48 - .80) 0.56 (.40 - .79)
ACE inhib 0.87 (.72 - 1.03) 0.95 (.75 - 1.19)
ARBs 0.83 (.44 - 1.56) 0.44 (.15 - 1.23)
Mortensen EM et al. Unpublished observations
Possible Mechanisms of Action for Statin Protection Against influenza
Statins interfere with mevalonate pathway decrease cholesterol synthesis and decrease activation of small GTPases
- Virus assembly and release
alter lipid raft microdomains decrease virus assembly and budding
- Anti-inflammatory / immunomodulatory effects
decrease NF-B and decrease AP-1 decrease cytokines, chemokines, cellular adhesions molecules; modify caspase activation and apoptosis
- Endothelial and epithelial cell function
increase eNOS increaseNO, vasodilatation, decrease oxidative stress;
alter actin cytoskeleton and intracellular tight junctions increase lung barrier function, decrease vascular leak
Other Agents to Consider for Pandemic Treatment and Prophylaxis
Other agents
- ACE inhibitors
- angiotensin-II receptor blockers(ARBs)
- phosphodiesterase inhibitors
- spironolactone
- chloroquine
These agents have anti-inflammatory and immunomodulatory activities
They could be used alone or in combination with
statins or each other
A Research Agenda for Statins and Influenza
*Epidemiological and clinical
- P&I in and out of influenza seasons
- hospitalization and mortality
- previous use only vs. continued use in hospital
*Animal models
- mice and ferrets
- H5N1 and 1918 reassortants
- treatment and prophylaxis
- cytokine profiles
- pathophysiological effects
*Cell-based infection
- basic molecular mechanisms of action
Could Statins and Other Agents Be Useful for Pandemic Influenza?
*The clinical and public health need for an effective agent is profound
*Experimental, clinical and epidemiological evidence suggests statins might be protective
*Generic statins are inexpensive and widely available worldwide
*The statins/influenza research agenda must be undertaken with a great sense of urgency
Preparing for an Imminent Pandemic
*Everyone should ask this question
If the pandemic is imminent, will my country be able to obtain adequate supplies of
- antivirals?
- vaccines?
- statins and other agents?
Preparing a Response to an Imminent Pandemic
?It is not enough to say, ?We are doing our best.? You have got to succeed in doing what is necessary.?
Winston Churchill
Will We Succeed in Doing What Is Necessary?
?Try again, fail again, fail better.?
Samuel Beckett
Worstward Ho
1983
Suggested Readings: Statins and Influenza
*Fedson DS. Pandemic influenza: a potential role for statins in treatment and prevention. Clin Infect Dis 2006, to be published (July 15th)
*Leser GP, Lamb RA. Influenza virus assembly and budding in raft-derived microdomains: a quantitative analysis of the surface distribution of HA, NA and M2 proteins. Virology 2005; 342; 215-27.
*Ludwig S, et al. Ringing the alarm bells: signaling and apopotosis in influenza virus infected cells. Cell Microbiol 2006; 8: 375-86.
*Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 2005; 4: 977-87.
*Beckman JA, Creager MA. The nonlipid effects of statins on endothelial function. Trends Cardiovasc Med 2006; 16: 156-62.
*Jacobson JR, et al. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 2005; 288: L1026-32.
Please see WHO CONSULATION FOR THE DEVELOPMENT OF A GLOBAL ACTION PLAN TO INCREASE THE SUPPLY OF PANDEMIC INFLUENZA VACCINES for an in-depth discussion of the problems of developing and distributing any effective H5N1 vaccination.
Asian European Conference on Avian Influenza 2006
Paris, 29-30 June 2006
Pandemic Influenza: A Potential Role for Statins in Treatment and Prophylaxis
David S. Fedson, MD
Prospects for Global Pandemic Vaccination: a WHO Assessment
?WHO is using international meetings to urge the international community to find ways to increase manufacturing capacity and ensure that developing countries have access to an effective vaccine at an affordable price. On current trends, however, most developing countries will have no access to a vaccine during the first wave of a pandemic and perhaps throughout its duration.?
--WHO, Global Programme on Influenza
Vaccine research and development, current status
November 2005
Six Interrelated Components of a Global Strategy for Pandemic Vaccination
Vaccine research and development
*Regulatory convergence
*Vaccine production capacity (GMP)
*IP issues and liability
*Vaccine purchasing, financing and distribution
*National vaccination programs
No institution or process exists or is planned that can do this at a global level!
Current Status of H5N1 Pandemic Vaccine Development
*Each company is developing its own H5N1 vaccine
*Government funding for clinical trials is limited, except for the US
*H5N1 vaccine viruses replicate poorly and are poorly immunogenic, even if adjuvanted
*In the event of an H5N1 pandemic, the global demand for vaccine will be >> 3-4 billion doses
Today, the world?s vaccine companies could produce enough doses of adjuvanted 30 mg HA vaccine in six months to vaccinate < 100 million people
Production capacity is unlikely to increase substantially within the next 3-5 years
Vaccination: the Likely Failure of a Top-down Response to a Pandemic
- Current efforts involve only a limited number of institutions, companies and governments, and only scientific, business and political elites are involved
- Management of the material and political logistics for global vaccination would require an elaborate international organization and be such a nightmare, it is not even being contemplated
*Pandemic vaccination will not be a realistic possibility for 85% of the world?s people who don?t live in countries with vaccine companies, and it will be difficult even for those who do
-
A Bottom-up Response to an Imminent Pandemic
*Elites have little or no control
*Uses large numbers of ordinary people in all countries
*Uses existing systems for delivering health care services to individuals as well as populations
*Uses existing resources that are affordable and already available worldwide
*Can be implemented on the first day of a pandemic
Statins: a Bottom-up Response to an Imminent Pandemic?
*Influenza increases AMIs, CHF and stroke
*Pro-inflammatory markers (CRP, TNF-a, IL-6) increase risk of CVD
*Influenza viruses up-regulate pro-inflammatory cytokines
*Influenza vaccination decreases AMIs, CHF and stroke
*Statins decrease CRP, TNF-a, and IL-6 and decrease risk of CVD
*Statins down-regulate pro-inflammatory cytokines
Statin-associated Protection in Syndromes with Cytokine Dysregulation
Author Study Statin Prev./Cont. Outcome Statin-assoc. reduction
Liappis (CID 2001) 388 cases continued bact-attr. mortality 87%
Almog (Circ 2004) 361 cases previous severe sepsis 87%
Kruger (ICM 2006) 438 cases continued bact-attr. mortality 92%
Hackam (Lancet 2006) 34,584/34,584 previous sepsis mortality 25%
Mancini (AJCC 2006) 4907/98,917 previous Hosp - COPD 26%
Protective Effect of Statins: Mortality from Bacteremia
*Retrospective study of 438 patients hospitalized with bacterial sepsis
*Conditional regression analysis to adjust for confounding variables
Bacteremia-attributable mortality
statin treated (6.1%) vs. not treated (18.3%)
OR = 0.29 (0.10 to 0.82)
continued Rx (1.8%) vs. no Rx (18.3%)
OR = 0.08 (0.01 to 0.60)
Kruger P et al. Intensive Care Med 2006; 32: 75-9.
Protective Effect of Statins: Population-based Study of Sepsis
*Ontario administrative database of patients discharged after hospitalization for acute cardiovascular disease
*Nested case-control study - 34,584 treated with statins and 34,584 propensity-matched untreated controls
Adjusted hazard ratios for statins (95% CIs)
All sepsis 0.81 (0.72 to 0.90)
Severe sepsis 0.83 (0.70 to 0.97)
Fatal sepsis 0.75 (0.61 to 0.93)
Hackam DG et al. Lancet 2006; 367: 413-8.
Protective Effect of Statins: Hospitalization for COPD in Quebec
Adjusted odds ratio
High-risk Low-risk
Treatment Myocard. revasc. NSAID Rx
cases/controls 946/18,774 4907/98,087
ACE inhibitors .87 .96
ARBs 1.04 .86
Statins .72 .74
Statins + ACEIs/ARBs .66 .77
Mancini GBJ et al. J Am Coll Card 2006; 47: 2554-60.
Statins and Pneumonia: An Epidemiological ?Signal of Protection?
*Population-based, nested case-control study of 1227 cases of pneumonia
*Three controls for each person on statins < 30 days
Adjusted OR (95% CI)
pneumonia hospitalization 0.63 (0.46 to 0.88)
30-day pneumonia mortality 0.47 (0.25 to 0.88)
Schlienger RG et al. Submitted for publication
Statins and Influenza-related Pneumonia: Reduction in 30-day Mortality
*8652 pneumonia patients ≥ 65 y.o. hospitalized October 1, 1998 - September 30, 1999
*Generalized linear mixed-effect model
Adjusted OR (95% CI)
Treatment (< 90d) Full year Flu season
Statins 0.62 (.48 - .80) 0.56 (.40 - .79)
ACE inhib 0.87 (.72 - 1.03) 0.95 (.75 - 1.19)
ARBs 0.83 (.44 - 1.56) 0.44 (.15 - 1.23)
Mortensen EM et al. Unpublished observations
Possible Mechanisms of Action for Statin Protection Against influenza
Statins interfere with mevalonate pathway decrease cholesterol synthesis and decrease activation of small GTPases
- Virus assembly and release
alter lipid raft microdomains decrease virus assembly and budding
- Anti-inflammatory / immunomodulatory effects
decrease NF-B and decrease AP-1 decrease cytokines, chemokines, cellular adhesions molecules; modify caspase activation and apoptosis
- Endothelial and epithelial cell function
increase eNOS increaseNO, vasodilatation, decrease oxidative stress;
alter actin cytoskeleton and intracellular tight junctions increase lung barrier function, decrease vascular leak
Other Agents to Consider for Pandemic Treatment and Prophylaxis
Other agents
- ACE inhibitors
- angiotensin-II receptor blockers(ARBs)
- phosphodiesterase inhibitors
- spironolactone
- chloroquine
These agents have anti-inflammatory and immunomodulatory activities
They could be used alone or in combination with
statins or each other
A Research Agenda for Statins and Influenza
*Epidemiological and clinical
- P&I in and out of influenza seasons
- hospitalization and mortality
- previous use only vs. continued use in hospital
*Animal models
- mice and ferrets
- H5N1 and 1918 reassortants
- treatment and prophylaxis
- cytokine profiles
- pathophysiological effects
*Cell-based infection
- basic molecular mechanisms of action
Could Statins and Other Agents Be Useful for Pandemic Influenza?
*The clinical and public health need for an effective agent is profound
*Experimental, clinical and epidemiological evidence suggests statins might be protective
*Generic statins are inexpensive and widely available worldwide
*The statins/influenza research agenda must be undertaken with a great sense of urgency
Preparing for an Imminent Pandemic
*Everyone should ask this question
If the pandemic is imminent, will my country be able to obtain adequate supplies of
- antivirals?
- vaccines?
- statins and other agents?
Preparing a Response to an Imminent Pandemic
?It is not enough to say, ?We are doing our best.? You have got to succeed in doing what is necessary.?
Winston Churchill
Will We Succeed in Doing What Is Necessary?
?Try again, fail again, fail better.?
Samuel Beckett
Worstward Ho
1983
Suggested Readings: Statins and Influenza
*Fedson DS. Pandemic influenza: a potential role for statins in treatment and prevention. Clin Infect Dis 2006, to be published (July 15th)
*Leser GP, Lamb RA. Influenza virus assembly and budding in raft-derived microdomains: a quantitative analysis of the surface distribution of HA, NA and M2 proteins. Virology 2005; 342; 215-27.
*Ludwig S, et al. Ringing the alarm bells: signaling and apopotosis in influenza virus infected cells. Cell Microbiol 2006; 8: 375-86.
*Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 2005; 4: 977-87.
*Beckman JA, Creager MA. The nonlipid effects of statins on endothelial function. Trends Cardiovasc Med 2006; 16: 156-62.
*Jacobson JR, et al. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 2005; 288: L1026-32.
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