2009 Pandemic Influenza: What Did We Learn and Where Do We ... · 2009 H1N1 Influenza Basics in Review 2009 Novel H1N1 Influenza Virus Genetically distinct from previous Seasonal

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2009 Pandemic Influenza:What Did We Learn and

Where Do We Go from Here?

C H R I S N E L S O N , M . D .

A S S O C I A T E P R O F E S S O R O F P E D I A T R I C S

D E P A R T M E N T O F P E D I A T R I C S

D I V I S I O N O F I N F E C T I O U S D I S E A S E S

U N I V E R S I T Y O F K E N T U C K Y C H A N D L E R M E D I C A L C E N T E R

L E X I N G T O N , K E N T U C K Y

Overview

2009 H1N1 Influenza Basics in Review

Characteristics of the 2009-2010 Pandemic

How Prepared Were We?

What Lessons Did We Learn? What Lessons Did We Learn?

Present State of the Pandemic

What Does the Future Hold?

2009 H1N1 Influenza Basics in Review

2009 Novel H1N1 Influenza Virus

Genetically distinct from previous Seasonal Influenza A H1N1 virus

Direct descendant of H1N1 Influenza virus that caused major human pandemics from 1918-1953

Had not circulated in the human population since 1957 Had not circulated in the human population since 1957 (52 years) but re-emerged from Mexican swine in March of 2009 to cause human pandemic

Contains human (20%), avian (30%) and swine (50%) influenza RNA gene segments, combined through genetic reassortment

Image Courtesy NewScientist.comImage Courtesy NewScientist.com

Antigenic Drift and Shift

Antigenic drift Minor point mutations in the genes coding for

hemagglutinin and neuraminidase glycoproteins that make the new, mutated circulating influenza viruses just different enough to your immune system from previously different enough to your immune system from previously encountered influenza strains that you can get sick with these “new” influenza strains.

Primary reason for annual vaccination

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Antigenic Drift and Shift

Antigenic Shift Abrupt, major changes to influenza A glycoproteins

occur, producing a novel new influenza A virus subtype that has not previously circulated in the human populationpopulation

Occurs through genetic “Reassortment”

Responsible for majorMixing of human and animal influenza A genes (usually occurs in swine- so-called “mixing vessels”) to create a new influenza A virus (called a reassortant virus)

epidemics and pandemics

Reassortment

Reassortment in Action

New New EnglEngl J Med.J Med. 2009;361:2252009;361:225--229229

WHO Pandemic Phases

Characteristics of the 2009-2010 Pandemic

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2009 H1N1 Influenza Pandemic Timeline

Pandemic Timeline Events February 24, 2009: a 6 month-old girl from northern Mexico develops a

Flu-like illness (later designated as “patient zero”) Early March, 2009: a respiratory illness sickens 60% of the town of La

Gloria, Veracruz, Mexico March 17, 2009: first confirmed case of H1N1 swine origin Influenza in

Mexicoh fi fi d f i i i i fl i March 28, 2009: first confirmed case of H1N1 swine origin influenza in a 9

year-old girl in Imperial County, California April 26, 2009: US declares Public Health Emergency April 27, 2009: WHO issues statement declaring Phase 4 Pandemic June 11, 2009: WHO declares Phase 6 Pandemic July 1, 2009: H1N1 cases in every state in US October 24, 2009: President Obama declares US State of National

Emergency Halloween, 2009: US Pandemic reaches its peak April, 2010: Resurgence in Southeast US and Hawaii, but only local, not

widespread activity; our much-anticipated “spring peak”

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Pandemic Flu 1918-1919 US Map at the Height of the 2009 Pandemic

2009 H1N1 Pandemic Flu Facts

Hospitalization rates for ages 5-17 were 2-5x that usually seen for seasonal Flu

Peak Flu activity the week of October 24-31 was highest ever recorded by CDCCDC estimates from Apr 2009 Feb 2010 CDC estimates from Apr 2009-Feb 2010: 59 million cases (Nl. 15-60 million annually) 265,000 hospitalizations (Nl. 200,000 ann.) 12,000 deaths (Nl. 36,000 ann.) 90% patients dying from H1N1 Flu had underlying medical

conditions (asthma, COPD, DM, Chronic Cardiovascular disease, morbid obesity, neurocognitive/neuromuscular disorders, pregnancy)

2009 H1N1 CDC Estimate

U.S. Cases

0-17 years ~19,000,000

18-64 years ~34,000,000

65 years and older ~6,000,000

U.S. Cases Total ~59,000,000 (Nl. Avg.15-60 million)

U.S. Hospitalizations

0-17 years ~85,000

18-64 years ~154 00018 64 years 154,000

65 years and older ~26,000

U.S. Hospitalizations Total ~265,000 (Nl. Avg. 200,000)

U.S. Deaths

0-17 years ~1250

18-64 years ~9200

65 years and older ~1550

U.S. Deaths Total ~12,000 (Nl. Avg. 36,000)

Source: CDC; data for period April 2009 through February 2010

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H1N1 Influenza Mortality at UK

Age Gender Underlying Diagnoses DOD

53 F Lymphoma 8/30/09

63 F COPD 10/6/09

48 M HIV/AIDS 10/8/09

41 M Multiple Myeloma 10/8/09

72 F COPD; History of Breast Cancer 10/23/09

47 F Lung Cancer 10/25/09

36 M Hepatitis B, Liver Failure, CHF 11/2/09

74 F Cirrhosis; History of CVA 11/2/09

57 M Lymphoma, s/p Bone Marrow Transplant

11/3/09

17 M Congenital Heart Disease 11/20/09



US Dept of Health and Human Services Report, 2009 Disaster preparedness of individual hospitals has improved

significantly throughout the country since the start of the HPP

The emergence of Healthcare Coalitions is creating a foundation for U.S. healthcare preparedness

Healthcare planning for catastrophic emergencies is in early stages; progress will require additional assistance and direction at the national level

Surge capacity and capability goals, assessment of training, and analysis of performance during actual events and realistic exercises are the most useful indicators for measuring preparedness

Hospitals Rising to the Challenge: The First Five Years of the U.S. Hospital Preparedness Program and Priorities Going Forward http://www.upmc-biosecurity.org/website/resources/publications/2009/pdf/2009-04-16-hppreport.pdf


US Dept of Health and Human Services Report, 2010

US hospitals should participate in a healthcare coalition that prepares and responds collaboratively to common medical disasters and Catastrophic Health Events (CHE)

Neighboring healthcare coalitions should establish links to Neighboring healthcare coalitions should establish links to enable regional exchange of health-care information and assets during a CHE

Triage sites should be established outside of hospitals and healthcare responders should be trained in CHE triage

The Next Challenge in Healthcare Preparedness: Catastrophic Health Events, January 2010http://www.upmc-biosecurity.org/website/resources/publications/2010/pdf/2010-01-29-prepreport.pdf


US Dept of Health and Human Services Report, 2010

The resources of the private sector should be harnessed to develop a patient transportation system for a CHE

Crisis standards of care should be expanded and promoted within and across stateswithin and across states

A national plan for various healthcare sector roles, responsibilities and actions in response to a CHE should be developed

The Next Challenge in Healthcare Preparedness: Catastrophic Health Events, January 2010http://www.upmc-biosecurity.org/website/resources/publications/2010/pdf/2010-01-29-prepreport.pdf


2005, 2007 Surveys of Hospital Infectious Disease Emergency Preparedness (all 50 U.S. States surveyed)

Most respondents had: a surge/influx of infectious patients plan and had

participated in disaster drills

24/7 IPAC support and an infection preventionist on their disaster committee

a prioritization plan for vaccine and antiviral medications

Rebmann T, et al. Am J Infect Control 2007;35:25-32, Rebmann T, et al. Am J Infect Control 2009;37:1-8

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• Many were stockpiling N95 respirators antiviral medications

• Less than 25% of facilities had: stockpiled ventilators, surgical masks, or patient linens; those that

did had <7 days worth of supplies

Cross-trained their staff to deal with absenteeismCross trained their staff to deal with absenteeism

Convened their ethics committee to discuss preparedness issues

Developed policies/procedures for altered standards of care during disasters

Rebmann T, et al. Am J Infect Control 2007;35:25-32, Rebmann T, et al. Am J Infect Control 2009;37:1-8

What Lessons Did We Learn?

Lessons Learned

2009 H1N1 Influenza Epidemiology is different than seasonal Influenza Predilection for young age (5-17 yrs) group and pregnant women 25% develop GI symptoms Many infected individuals experienced mild, non-debilitating symptoms which

facilitated spread in schools and the workplace Increased mortality in morbidly obese individuals

I fl i d ti d di t ib ti th d d t b Influenza vaccine production and distribution methods need to be modernized

Key supply stockpiles are critical (antivirals, masks, etc.) It could have been much, much worse

Low virulence virus, did not mutate like 1918 ancestor (yet) This was not Avian Influenza

Important to be prepared, have a detailed Pandemic Plan Stay current with and respond to rapidly changing situations and be

able to rapidly disseminate information throughout organizations

Lessons Learned

We need enhanced national and international surveillance in both human and animal populations Would allow for early detection and possible anticipation of next

pandemic strain to emerge

Could facilitate vaccine development earlier in the evolution of a new d ipandemic

Lesson Re-Learned: Both seasonal and pandemic influenza viruses are capable of causing tremendous morbidity and mortality

Public trust in and acceptance of influenza vaccine continues to be an issue

Edwards, KM. Infectious Diseases in Children, March 2010

Influenza-Like Illness (ILI)

Rapid Onset of Temperature >100.0 F Cough Sore throat

In the absence of a known cause other than influenza

Additional symptoms associated with seasonal and Novel H1N1 Influenza that should be assessed in patients presenting with ILI: Fatigue, body aches, chills, congested/runny nose,

headache 24% of patients with H1N1 Flu will also have

vomiting and/or diarrhea

2009 H1N1 Influenza Symptom Progression

UK physician, previously healthy, only underlying condition: exercise-induced asthma

Day #1: 11/4/09, 4 pm; Scratchy throat Day #2: 11/5/09; awoke with congestion, mild sore

throat, but spent a productive day at work Day #3: 11/6/09 awoke with congestion a bit worse, decided to stay

home 10 am: rapid onset of cough, diffuse myalgias and chills 11:30 am: IMG Clinic for assessment (Temp 99.4°F),

PCR testing and oseltamivir Rx for presumed influenza Progressed to severe myalgias, fatigue, grossly

productive cough, TMax 100.2°F that evening

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2009 H1N1 Influenza Symptom Progression

UK Physician Day #4: 11/7/09; Influenza A RT-PCR resulted positive.

Worsening of all symptoms with addition of nausea, repeated fever spikes, TMax 101.2°F

Day #5: 11/8/09; continuation of sx’s, TMax 100.4°F, slight easing of sx’s by evening except productive cough

Day #6: 11/9/09; almost complete resolution of myalgias, but continued grossly productive cough, afebrile all day

Day #7: 11/10/09; chills, fever 100.4°F at 3 am, but no further daytime fevers and myalgias completely resolved; cough less productive

Day #8: 11/11/09; afebrile >28 hours, occasional scant productive cough, returned to work

Lessons Learned

Flu happens even when you are very careful You can be infected with this particular Flu virus

for hours to days before developing classic influenza symptoms, unwittingly spreading it to others; this is unlike most seasonal Fluot e s; t s s u e ost seaso a u

Who said Novel H1N1 is a milder illness? Nausea with this Flu virus makes oral hydration

and oral antipyresis and analgesia a real challenge; with vomiting and diarrhea, maintenance of hydration would be impossible

Flu is awful- GET YOUR VACCINE!

Present State of the Pandemic

Present Situation

Remain at WHO Pandemic Phase 6 99.4% typed influenza isolates submitted to CDC this season

are 2009 Pandemic H1N1 What happened to “seasonal” Flu?

H3N2 likely gone Previous seasonal H1N1 replaced by new Pandemic H1N1 strain

2009 Pandemic H1N1 virus has still not significantly mutated 2009 Pandemic H1N1 virus has still not significantly mutated (yet)

2009 Pandemic H1N1 antiviral susceptibility has remained very stable: 99.8% susceptible to oseltamivir 100% susceptible to zanamivir

Although delivery was late, the new H1N1 vaccine was highly immunogenic and safe

March-April 2010 has brought resurgent Flu activity in Southeast US and Hawaii but only local activity is being seen

Present US Situation

What Does the Future Hold?

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The Future

Development of antiviral resistance

Advances in treatment IV peramivir

Lung bypass Lung bypass

Advances in Prevention New Flu vaccine technology

Mandated Flu vaccination for healthcare workers

The Future: Antiviral Agents for Influenza

Adamantanes/M2 Ion Channel Inhibitors Amantadine (Symadine, Symmetrel) Rimantadine (Flumadine)

Neuraminidase (sialidase) Inhibitors Oseltamivir (Tamiflu) Oseltamivir (Tamiflu) Zanamivir (Relenza)

RNA Polymerase Inhibitors Ribavirin (Copegus, Rebetol, Ribasphere, Vilona and

Virazole) Taribavirin (Viramidine)

Peramivir IV; emergency use authorization (EUA) by FDA 10/25/09

Peramivir

Only intravenous influenza antiviral medication available Peramivir is authorized for the following patients who are

admitted to a hospital: Adult patients for whom therapy with an IV agent is clinically

appropriate, based upon one or more of the following: patient not responding to either oral or inhaled antiviral therapy, or drug delivery by a route other than IV (e.g. enteral oseltamivir or

inhaled zanamivir) is not expected to be dependable or is not feasible, or

the clinician judges IV therapy is appropriate due to other circumstances.

Pediatric patients for whom an IV agent is clinically appropriate because: patient not responding to either oral or inhaled antiviral therapy, or drug delivery by a route other than IV (e.g. enteral oseltamivir or

inhaled zanamivir) is not expected to be dependable or is not feasible

Artificial Lung

Artificial Lung

Double Lumen catheter

Portable pump system

CO2/O2 gas exchanger

Right Int. Jugular placement into SVC/IVCp /

Advantages over ECMO Decreased cost

Increased portability

Longer-term use capability

Fewer skilled healthcare staff required

Still Investigational

ACIP on Flu Vaccination 2010-2011

2010-2011 Flu Vaccine Components

2009-2010 Seasonal Vaccine 2010-2011 Vaccine

A/Brisbane/59/2007 (H1N1) A/California/7/2009 (H1N1)*

A/Brisbane/10/2007 (H3N2) A/Perth/16/2009 (H3N2)

*2009 H1N1 Pandemic Influenza virus

Universal Influenza Vaccination Recommended 50% of adults aged 19-49 have indication for annual vaccination

Vaccinating the entire population would simplify current complicated recommendations that create confusion

Public education on vaccine efficacy and safety needed

B/Brisbane/60/2008 (Victoria lineage) Same strain retained

CDC/ACIP Home Page: http://www.cdc.gov/vaccines/recs/ACIP/default.htm

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The Future: New Influenza Vaccines

Present vaccine production technology 1931: Flu virus first grown in fertilized chicken’s eggs

1940’s: US Military developed first influenza vaccines using egg inoculation method

Production technology in the US using inoculation of chicken Production technology in the US using inoculation of chicken eggs has not changed significantly since the 1940’s


Present egg-based vaccine production technology: Egg shell punctured

Influenza virus injected into allantoic fluid surrounding embryoy

Puncture site re-sealed

Egg incubated to allow infection to progress

Eggs harvested, progeny virus purified and inactivated, vaccination produced


Alternative strategies for Influenza vaccine development: Live cell culture-based methodology

First described mid-1990’s

Live seed virus inoculated into live tissue culture

Virus attaches to, invades and multiplies in cells

Cells harvested, virus purified and inactivated

Vaccine formulated and distributed

e.g. Optaflu from Novartis


Live cell culture-based methodology advantages over embryonated chicken egg production method: Cleaner production process

Eliminates reliance on procuring chicken eggs

Production can be scaled up much more quickly to respond to a pandemic (egg: 3-6 months vs. cell-based: 1-2 months)

Avoids egg allergy issue presently a problem with egg-based vaccines

Five vaccine companies have been awarded large HHS contracts in 2006 to develop cell culture vaccines (Baxter, GlaxoSmith-Kline, Novartis, Sanofi-Pasteur) One has terminated its contract, another placed its efforts on hold

One company (Sanofi Pasteur) will stick with egg-based method methodology (presently makes most US Flu vaccine)


Hemagglutinin synthesis using baculovirus to produce an influenza virus-like particle (VLP) Genes (hemagglutinin (HA), or combinations of hemagglutinin,

neuraminidase, and M1 matrix protein) are extracted from influenza virus and inserted into a baculovirus

Caterpillar (Fall Army Worm) cells are infected with Caterpillar (Fall Army Worm) cells are infected with baculovirus and begin producing hemagglutinin proteins

Proteins are extracted and formulated in phosphate buffered saline without preservatives or adjuvants

Phase I and II trials have demonstrated safety and efficacy in healthy adults, the elderly and non-Hodgkin’s lymphoma pts.

FluBlok™ (Protein Sciences Corporation, Meriden, CT)

Lakey DL. J Infect Dis 1996 174(4):838-41Treanor JJ J Infect Dis 2006;193(9):1223-8Safdar A. J Infect Dis 2006;194(10):1394-7

Bright, RA, et al. Vaccine 2007;25(19):3871-8


Recently-discovered alternative viral proteins targeted by the human immune system 10 human antibiodies have been identified that target the stalk

(rather than the head) portion of the hemagglutinin (HA) protein

Studies in mice infected with lethal doses of influenza given 3 of these 10 antibodies neutralized 80 100% of infectionsthese 10 antibodies neutralized 80-100% of infections

Influenza HA stalk proteins are highly conserved among all influenza viruses (human and animal) and are very genetically stable

These results could lead the way to: Influenza vaccines that do not need to be reformulated each year (no need

to consider antigenic shift or drift)

Production of monoclonal HA stalk protein neutralizing antibodies that could be used to treat patients with serious and life-threatening influenza infections

Sui J. Nat Struct Mol Biol. 2009;16(3):265-73

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Intradermal delivery of influenza vaccine Developed in an attempt to improve immunogenicity of influenza

vaccination, particularly in older adults in whom immune response to vaccine often is attenuated

May be more effective than intramuscular delivery due to stimulation f d d iti ll hi h i li d ti ti llof dendritic cells, which are specialized antigen presenting cells

Clinical trial of adults >60 years of age demonstrated higher antibody titers, seroprotection rates and seroconversion rates compared with those receiving intramuscular Flu vaccine

Higher rates of local injection site reactions, particularly redness but not pain, were seen with intradermal vaccination vs. intramuscular vaccination

Example: Intanza®/ID-flu® (Sanofi-Aventis)Holland D, et al. J Infect Dis 2008;198(5):650-8


Dosage alterations of influenza vaccine High (60 mcg HA) vs. standard (15 mcg HA) dose vaccine

study in adults >65 years of age: Improved seroconversion rates

Increased mean HA inhibition titers

Increased mild-moderate local reactions with high dose vaccine

“Split” (half) dose vaccination Produces equivalent protective HA titers (>1:40) when compared

to full-dose vaccine in adults who have previously been vaccinated

Equal or higher titers among women 18-49 years of age vs. men who receive full dose vaccine

Unacceptably low titers in some subjects 50-64 years of age

Falsey AR. J Infect Dis 2009;200(2):172-80Keitel WA. J Infect Dis. 2008;198(7):1016-8Engler RJ. Arch Intern Med. 2008;168(22):2405-14


Adjuvanted vaccines Adjuvant

Definition: A vaccine adjuvant is a substance that is added to the vaccine to increase the body's immune response to the vaccine; an adjuvant often allows for p ; jsmaller amounts of the inactivated virus or bacterial components to be used in the production of a vaccine

Rationale: A major problem with the development of an effective vaccine against avian influenza (H5, in particular) has been poor immunogenicity in humans; this has rekindled interest in adjuvant use in influenza vaccines

Sources: CDC, UpToDate


Adjuvanted Vaccines Examples:

Aluminum salts, such as aluminum hydroxide, aluminum phosphate, and aluminum potassium sulfate are the only adjuvants currently licensed for use in the US

US-licensed vaccines containing aluminum salt adjuvants: US licensed vaccines containing aluminum salt adjuvants: hepatitis A, hepatitis B, diphtheria-tetanus-pertussis (DTaP, Tdap) Haemophilus influenzae type b (Hib), human papillomavirus (HPV) and pneumococcus

Oil (squalene)-in-water emulsions such as MF59® (Novartis)

Seasonal influenza/MF59® (Fluad®) H5N1, MF59-adjuvanted vaccine, egg-derived

(AFLUNOV®/FOCETRIA®)

H5N1, MF59-adjuvanted vaccine, cell culture-derived (OPTAFLU®

platform)

The Future: Mandated Influenza Vaccination

Study-proven benefits of vaccinating HCW: Decreased absenteeism

Decreased mortality among patients (nursing home setting)

Financial savings to healthcare institutions

Vaccination rates in US healthcare workers: 40-40%4 4

Organizations supporting mandatory Flu vaccination Infectious Diseases Society of America (IDSA)

National Patient Safety Foundation (NPSF)

US Department of Defense mandates flu vaccine for: All military healthcare providers

All civilian healthcare personnel who provide direct patient care in department of defense treatment facilities

The Future: Mandated Influenza Vaccination

Healthcare Institutions mandating annual Flu vaccine: Cook Count Health and Hospitals System (Chicago)

Barnes-Jewish Healthcare, St. Louis, Hospital Corporation of America (HCA), many others*( ), y

How it is done: Gentle Approach- use of declination form to opt out, decliners

must wear surgical masks for duration of Flu season and are terminated if they do not comply with mask usage

Get-Tough Approach- opt out only for religious reasons, allergy to egg or previous vaccine, Guillan-Barre; refusal to accept vaccination results in termination of employment

*Immunization Action Coalition’s Honor Roll: http://www.immunize.org/laws/influenzahcw.asp

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The Future: Final Thoughts…

Enhanced Influenza Surveillance in Human and Animal Populations

Expedited vaccine approval by FDA, production by pharmaceutical companies and delivery by the

tgovernment

Improved antiviral stockpiles and rapid delivery

Public education

Avian influenza: the specter on the horizon

Helpful Resources

UK Healthcare Pandemic Influenza Primer, Assessment Algorithm, FAQ’s: http://www.uky.edu/EM/swineflu.htm (click “For Medical Professionals”)

CDC Seasonal Influenza Website: http://www.cdc.gov/flu/ CDC 2009 Novel H1N1 Influenza Website:

http://www.cdc.gov/h1n1flu/ World Health Organization (WHO) Website: g ( )

http://www.who.int/csr/disease/swineflu/en/index.html Kentucky Department of Public Health Site:

http://healthalerts.ky.gov/ Flu.Gov: http://www.flu.gov/ Helpful Pandemic Planning Tools: CDC Pandemic Influenza Planning Checklist for Hospitals:

http://www.flu.gov/professional/hospital/hospitalchecklist.pdf CDC Pandemic Influenza Planning Checklist for Medical Offices:

http://www.pandemicflu.gov/professional/pdf/medofficesclinics.pdf CDC’s 10 Action Steps for Medical Offices and Outpatient Facilities:

http://www.cdc.gov/h1n1flu/10steps.htm

Documents

2009 Pandemic Influenza: What Did We Learn and Where Do We ... · 2009 H1N1 Influenza Basics in Review 2009 Novel H1N1 Influenza Virus Genetically distinct from previous Seasonal