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
Antiviral Chemoprophylaxis
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
Antiviral Chemoprophylaxis
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
The Future: New Influenza Vaccines
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
The Future: New Influenza Vaccines
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
The Future: New Influenza Vaccines
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)
The Future: New Influenza Vaccines
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
The Future: New Influenza Vaccines
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
The Future: New Influenza Vaccines
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
The Future: New Influenza Vaccines
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
The Future: New Influenza Vaccines
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
The Future: New Influenza Vaccines
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