2009 pandemic influenza: what did we learn and where do we ... · overview 2009 h1n1 influenza...

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 SD 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 K H E A L T H C A R E E N T E R P R I S E M E D I C A L D I R E C T O R F O RI N F E C T I O N P R E V E N T I O N A N D C O N T R O L

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

2009 Pandemic Influenza:What Did We Learn and

Where Do We Go from Here?

Overview

2009 H1N1 Influenza Basics in Review

Characteristics of the 2009-2010 Pandemic

Present State of the Pandemic

What Lessons Did We Learn?

Influenza 2010-2011 SeasonTesting, Treatment, Prevention

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 (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.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 encountered influenza strains that you can get sick with these “new” influenza strains.

Primary reason for annual vaccination

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 population

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

Characteristics of the 2009-2010 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 CDC

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 ~154,000

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

H1N1 Influenza Mortality at UKCMC

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

Present State of the Pandemic

Pandemic Timeline: Present Situation

June 23, 2010: U.S. Public Health Emergency Declaration expired

August 10, 2010: WHO declared end to pandemic

Internationally, 2009 H1N1 and seasonal (H3N2, Influenza B) viruses are co-circulating

2009 H1N1 demonstrating expected seasonal pattern, and will likely circulate for several years to come

Present Situation

99.4% typed influenza isolates submitted to CDC last season were 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 (yet)

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

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

What Lessons Did We Learn?

Lessons Learned

2009 H1N1 Influenza Epidemiology is different than previous seasonal Influenza Mortality and morbidity affected persons of young age (5-17 yrs) and pregnant women

disproportionately 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

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 pandemic

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

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 Flu

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 combined, maintenance of hydration would be impossible

Flu is awful- GET YOUR VACCINE!

Influenza 2010-2011 SeasonTesting, Treatment, Prevention

2010-2011 Flu Season: What to Expect

Expect a more “typical” Flu season, with sporadic cases throughout summer and fall months, and a typical winter upswing and peak in cases

The 2009 H1N1 Flu strain will predominate the influenza landscape

Vaccine will be available before onset of Flu season, and the targeted 170 million doses of vaccine will likely be sufficient to satisfy U.S. demand

Laboratory Testing for Influenza

Rapid Office-based EIA tests

Good: Fast turn-around; can give patients a “result”

Bad: Very low sensitivity (10-70%)

Viral Culture

Good: gold standard

Bad: 24-48 hour turn-around, can’t type or subtype

Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)

Good: highly sensitive and specific, rapid turn-around, tests for type and subtype available

Bad: Can’t be done in office at point of care, expensive

Treatment of Influenza

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

Rimantadine (Flumadine)

Neuraminidase (sialidase) Inhibitors 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

Influenza Antiviral Susceptibilities

Influenza Virus Type

Antiviral Previous Seasonal H1N1

2009 Pandemic H1N1

SeasonalH3N2

SeasonalInfluenza B

AmantadineRimantadine

Susceptible Resistant Resistant Resistant

Oseltamivir Resistant Susceptible Susceptible Susceptible

Zanamivir Susceptible Susceptible Susceptible Susceptible

Influenza 2010-2011 Season

Who to Treat- Pediatrics

Any child hospitalized with presumed influenza

Influenza infection of any severity in children at high risk, regardless of influenza immunization status

any otherwise healthy child with influenza infection for whom a decrease in duration of clinical symptoms is felt to be warranted by his or her provider.

Clinical Judgment is an important factor

Start treatment early; do not wait for test results

Those presenting with an uncomplicated Flu-like illness do not require treatment unless they are at higher risk of influenza complications

Pediatrics 2010;126(4):1-11

Antiviral Chemoprophylaxis

Definition: prescription of antiviral medications to individuals who

have experienced a close contact exposure and

are at high risk for serious illness with influenza or who work in a setting (such as the healthcare setting) with high potential for spread of their influenza infection to other susceptible and high risk individuals

can prevent exposed individuals from developing symptoms of influenza and can reduce their risk of spreading influenza to others, while simultaneously allowing the exposed individual’s immune system to develop protective antibodies to the influenza virus


Infectious Period: begins 1 day before an infected individual develops

symptoms to up to 7 days after they become ill

Children, especially younger children, and immunocompromised individuals can shed influenza virus for longer periods

Practical definition used for chemoprophylaxis decisions:

CDC defines the infectious period for influenza is as 1 day before until 24 hours after fever ends


CDC recommends post-exposure antiviral chemoprophylaxis can be considered for the following: Persons who are at higher risk for complications of influenza and

are a close contact of a person with confirmed, probable, or suspected 2009 H1N1 or seasonal influenza during that person’s infectious period.

Health care personnel, public health workers, or first responders who have had a recognized, unprotected close contact exposure to a person with confirmed, probable, or suspected 2009 H1N1 or seasonal influenza during that person’s infectious period

Actual agents prescribed should be based on viruses circulating in the community

No prophylaxis indicated for exposures >48 hours prior

2010-2011 Influenza Vaccination: What’s New

All persons >6 months of age are recommended to receive influenza vaccination annually

The number of vaccinations for children 6 months to 8 years of age varies by vaccination history (next slide)

The 2009 pandemic H1N1 influenza virus replaces the former seasonal H1N1 influenza virus in this season’s vaccine

MMWR 2010;59(RR-8):1-62

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)

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

Pediatrics 2010;126(4):1-11

2010-2011 Influenza Vaccination: What’s New

Expanded age indications for previously approved influenza vaccines Fluarix (GlaxoSmithKline), persons >3 years of age

Afluria (CSL Biotherapies), persons >6 months of age

Newly-approved Influenza vaccines High dose (60 mcg) trivalent vaccine (Fluzone High Dose,

Sanofi-Pasteur), persons >65 years of age

New inactivated vaccine (Agriflu, Novartis), persons >18 years of age

MMWR 2010;59(RR-8):1-62

ACIP 2010 Influenza Vaccine Recommendations

When vaccine supply is limited, vaccination efforts should focus on delivering vaccination to persons who: are aged 6 months–4 years (59 months);

are aged ≥50 years;

have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus);

are immunosuppressed (including immunosuppression caused by medications or by human immunodeficiency virus);

are or will be pregnant during the influenza season;

are aged 6 months–18 years and receiving long-term aspirin therapy and who therefore might be at risk for experiencing Reye syndrome after influenza virus infection;

are residents of nursing homes and other chronic-care facilities;

are American Indians/Alaska Natives;

are morbidly obese (body-mass index ≥40);

are health-care personnel;

are household contacts and caregivers of children aged <5 years and adults aged ≥50 years, with particular emphasis on vaccinating contacts of children aged <6 months; and

are household contacts and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza.

MMWR 2010;59(RR-8):1-62

What Does the Future Hold?

The Future

H1N1 virus mutation to enhance virulence Development of antiviral resistance is inevitable

Important to stay current with resistance trends that influence treatment

Mutation to resemble H1N1’s 1918 ancestor in pathogenesis

Advances in treatment IV peramivir; Future oral formulation?

Artificial Lung; possible alternative to ECMO?

Advances in Prevention New Flu vaccine technology

Mandated Flu vaccination for healthcare workers

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 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 embryo

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 were 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 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):838-41

Treanor JJ J Infect Dis 2006;193(9):1223-8

Safdar 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 antibodies have been found that target the stalk(rather than the head) of the hemagglutinin (HA) protein

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

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


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 of 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):172-80

Keitel WA. J Infect Dis. 2008;198(7):1016-8

Engler 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 smaller 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: 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%

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 County Health and Hospitals System (Chicago)

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

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, h/o Guillan-Barre; refusal to accept vaccination results in termination of employment

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

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 government

Improved antiviral stockpiles and rapid delivery

Public education about influenza, vaccines

Avian influenza: the specter on the horizon

Helpful Resources

*CDC Seasonal Influenza Website: http://www.cdc.gov/flu/ *ACIP 2010 Flu Vaccine Recommendations:

http://www.cdc.gov/mmwr/pdf/rr/rr5908.pdf *AAP Policy Statement Recommendations, Flu 2010-2011:

http://pediatrics.aappublications.org/cgi/reprint/peds.2010-2216v1 World Health Organization (WHO) Website:

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

http://www.cdc.gov/flu/

http://www.cdc.gov/mmwr/pdf/rr/rr5908.pdf

http://pediatrics.aappublications.org/cgi/reprint/peds.2010-2216v1



http://www.who.int/csr/disease/swineflu/en/index.html

http://healthalerts.ky.gov/

http://www.flu.gov/

http://www.flu.gov/professional/hospital/hospitalchecklist.pdf

http://www.pandemicflu.gov/professional/pdf/medofficesclinics.pdf

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

2009 pandemic influenza: what did we learn and where do we ... · overview 2009 h1n1 influenza...

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