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The Science of Influenza Vaccine Development: Implications for the Public Health Practitioner. David Cho, PhD, MPH Program Officer, Influenza Vaccine Development Respiratory Disease Branch, DMID, NIAID. Goals of the Presentation.

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The Science of Influenza Vaccine Development: Implications for the Public Health Practitioner

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The Science of Influenza Vaccine Development: Implications for the Public Health Practitioner

David Cho, PhD, MPH

Program Officer, Influenza Vaccine Development

Respiratory Disease Branch, DMID, NIAID

Goals of the Presentation

  • Describe the basic scientific differences between seasonal and pandemic influenza

  • Explain what researchers are doing to overcome the challenges that a pandemic strain brings

  • Explain what practitioners should consider in preparation for a pandemic

Characteristics of a Pandemic Influenza Virus

  • Influenza A virus with a novel hemagglutinin or novel hemagglutinin and neuraminidase in man

  • Susceptibility (no neutralizing antibody) to the novel virus in a large proportion of the population

  • Demonstration of the virus to cause and spread person-to-person in a sustained fashion

Influenza Virus Nomenclature

Source: Subbarao/Murphy

Previous pandemics

1918 H1N1 transferred from birds?: > 40 million deaths worldwide

1957 H2N2 avian-human reassortant: > 2 million deaths

1968 H3N2 avian-human reassortant: > 1 million deaths

Seasonal influenza

Millions of human cases; hundreds of thousands of hospitalizations yearly in the US alone

Influenza and pneumonia: 7th leading cause of mortality in the US in 2002

20,000 to 40,000 deaths annually US

250,000 to 500,000 deaths annually worldwide

Clinical Burden of Influenza Virus Morbidity and Mortality

H5N1 Avian influenza

290+ documented human cases

170+ deaths

Over 3 ½ + years, fewer than 100 documented cases/ year

Seasonal influenza

Millions of human cases; hundreds of thousands of hospitalizations yearly in the US alone

Influenza and pneumonia: 7th leading cause of mortality in the US in 2002

20,000 to 40,000 deaths annually US

250,000 to 500,000 deaths annually worldwide

Clinical Burden of Influenza Virus Morbidity and Mortality (continued)

Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO 11 April 2007

> 50% mortality

Cases and countries shown in gold for events since January 2007. WHO reports only laboratory-confirmed cases.

H5N1 outbreaks in 2005 and major flyways of migratory birds

(situation on 30 August 2005)

Mississippi Americas flyway

East Atlantic flyway

Atlantic Americas flyway

Black Sea/ Mediterranean flyway

Central Asia flyway

Districts with H5N1 outbreaks since January 2005

East Africa West Africa flyway

Pacific Americas flyway

East Asia/ Australian flyway

Sources: AI outbreaks: OIE, FAO, and Government sources. Flyways: Wetlands International

Schematic Version of Influenza Virus (continued)

  • Influenza A subtypes:

    • 16 Hemagglutnins (HA)

    • 9 Neuramindases (NA)

  • All subtypes: endemic in birds

  • H1N1, H2N2, H3N2: endemic in people

  • HA trimers: Binds sialic acid and fuses viral and cell membranes

  • NA tetramers: Removes sialic acid to prevent adherence to self or cell during budding

  • RNA Polymerases (PB1, PB2, PA) attached to each RNP

  • Nucleoprotein (NP) binds RNA and Matrix protein (M1)

  • On viral and infected cell surface:

  • M2 tetramers

  • Hydrogen ion channel

  • In infected cell:

    • NS1

    • Binding host proteins

    • Role in IFN resistance

Schematic Version of Influenza Virus(continued)

Emergence of New Human Influenza Subtypes

H5N1 Virulence Factors in Mammals

  • HA with multibasic amino acid motif (RERRRKKR) at the HA1-HA2 cleavage site

  • Polymerase genes adapted to mammalian host

    • 1997 H5N1 with PB2 lysine at AA position 627

    • 2004 H5N1 with polymerases from human source more virulent in ferrets than same H5N1 with polymerases from avian source

  • NS1 gene adapted for mammalian host

    • Inhibition of interferons

    • Increased TNF alpha

Source: Salomon et al. JEM 2006;203:689.

Source: Horimoto and Kawaoka. Nature Reviews Microbiology, 2005

What Makes the HA Highly Pathogenic?


Common Features of H5N1 in Humans

  • Contact with sick/dying poultry

  • Frequently healthy young person

    • Average age <18

  • Incubation period 2–4 days from probable exposure

  • Presenting symptoms fever, dyspnea, cough

  • Diarrhea more common than expected with influenza

  • Leukopenia/lymphopenia/thrombocytopenia

  • Metabolic abnormalities

Common Features of H5N1 in Humans (continued)

  • High frequency of progressive pneumonia

    • Mostly primary viral

    • Occasional contribution of bacteria?

      • (Staphylococcus aureus and Haemophilus influenzae)

  • Hepatic necrosis and acute tubular necrosis

  • High mortality rate in spite of antiviral/steroid/antibacterial treatment

Common Features of H5N1 in Humans(continued)

  • Diffuse activation of the innate immune system (“cytokine storm”) with increased levels of:

    • Interleukin 1 beta

    • Interleukin 6

    • Interleukin 8

    • Tumor Necrosis Factor alpha

    • Interferon alpha

    • Interferon gamma

    • Interferon inducible protein 10

    • Soluble Interleukin 2 receptor

    • Monocyte chemoattractant protein 1

Chest Radiographs of Patient with Severe H5N1 Influenza Pneumonia: Vietnam, 2004

Source: Tran et al. N Engl J Med 350:1171, 2004

Additional H5N1 Virulence Factors in Humans

  • HA receptor binding

    • Two ketosidic linkages of sialic acid to galactose: alpha 2,3 and alpha 2,6

    • Avian HA preference for alpha 2,3 linkage

    • Human upper airway predominantly alpha 2,6 linkage

    • Human lower airway more abundant in alpha 2,3 linkage

  • Possibly contributes to the high incidence of primary viral pneumonia caused by H5N1 viruses

Source: Shinya et al. Nature 2006;440:435

Evidence for Person-to-Person H5N1 Transmission (Not Sustained)

  • Possible instances of infection of health care workers during 1997 outbreak in Hong Kong

  • Family clusters Vietnam, Thailand* and Indonesia**

  • Cluster in Indonesia suggests human to human to human transmission before the chain extinguished***

(* Ungchusak et al. N Engl J Med 2005;352:333-340

** Kandun et al. N Engl J Med 2006;355:2186-2194

***Normile Science 2006;312:1855)

Detection of H5N1 Viruses: Lessons from Recent Experiences

  • Throat samples may give higher yield than nasal samples, but both worth examining

  • Rapid tests poor negative predictors and lack specificity

    • But microarray methods improving and may provide sensitivity and specificity

  • Polymerase chain reaction (PCR) increases sensitivity but success depends on the primers used for amplification

  • Laboratory confirmation generally accepted

    • Viral culture

    • Positive PCR for H5N1 RNA

      • (see

    • Positive immunofluoresence using a monoclonal antibody for H5

    • 4-fold or greater rise in H5-specific antibody in paired acute and convalescent sera


Antiviral Therapies for Influenza

Antiviral Agents for Treatment of H5N1 Viruses

  • Early treatment recommended for suspect cases but efficacy, optimum dose, and duration uncertain

  • Treatment of choice is a neuraminidase inhibitor

    • Oseltamivir has been most frequently used

      • 5 days treatment of 75 mg twice daily for adults and dose decreases for children dependent on body mass is standard

      • Higher doses may be considered by some authorities but no prospective studies

  • Oseltamivir resistance during treatment may not result in resistance to zanamivir

Antiviral Agents for Prophylaxis of H5N1 Viruses

  • Oseltamivir 75 mg once daily for 7–10 days may be considered for significant post exposure prophylaxis

    • But rationale is based on evidence from studies with other influenza A virus subtypes

  • Potential recipients would be poultry workers/cullers, health care workers, household contacts

Antiviral Agents for Treatment of H5N1 Viruses

  • Zanamivir administered as inhaled powder, which may be difficult with respiratory symptoms

  • Amantadine/rimantadine resistance common in Asian H5N1 viruses

    • Possibly from agricultural use of drugs

  • Amantadine/rimantadine susceptibility of some recent strains (African/European/Middle East)

    • May be clade specific

    • May be a role for M2 inhibitors

  • Other drugs (ribavirin and interferon) may also be considered but no value clearly documented

  • Clinical studies in progress

    • Peramivir (injectable neuraminidase inhibitor)

    • CS8958 (once daily neuraminidase inhibior)

    • 705 (polymerase inhibitor)

    • Studies may start soon with FluDase (sialidase to remove viral receptors)

Pandemic Influenza Preparedness: Complementary Roles Within DHHS

NIH Trials with sanofi pasteur H5N1 A/Vietnam/1203/2004

  • Adults (18 – 64y; 7.5, 15, 45, 90ug)*

    • Immune response observed at all dose levels after a single dose, unadjuvanted vaccine

    • 2 x 90mcg doses produced most frequent and highest antibody responses

    • April 17, 2007 FDA approval of sanofi vaccine at 90 mcg dose for persons exposed to H5N1

  • Additional studies in elderly (65y+; 45 or 90ug); children (2–9y; 45ug)

    • Immunogenicity results similar to adults

      (* Treanor et al. N Engl J Med 2006; 354:1343-1351)

Dose Optimization of Inactivated H5N1 Vaccines: Aluminum Adjuvants

  • Controlled trials completed or planned

    • CSL Australia: subvirion vaccine +/- AlPO4

    • Baxter Austria: whole virus +/- AlOH

    • Novartis UK: subunit vaccine +/- AlOH

    • Sanofi France and US: subvirion vaccine +/- AlOH in adult and elderly populations

  • Summary

    • Vaccines well tolerated with or without aluminum adjuvant

    • Immunogenicity: Aluminum adjuvants do not show a clear advantage over vaccine alone

Dose Optimization of Inactivated H5N1 Vaccines: Other Adjuvants

  • Trials with other adjuvants

    • GSK: subvirion vaccine +/- AS (proprietary adjuvant system)

    • Novartis UK: subunit vaccine with MF59 (proprietary adjuvant system

  • Summary

    • Vaccines well tolerated with or without adjuvant but somewhat increased local reactogenicity

    • Immunogenicity: Adjuvants result in more frequent and higher antibody responses

Dose Optimization of Inactivated H5N1 Vaccines: Route

  • Trials with other alternate route of administration

    • Sanofi subvirion vaccine given intradermal (ID) at reduced dose or intramuscular (IM) at higher dose

  • Summary

    • Vaccines well tolerated but increased local reactogenicity with intradermal administration

    • Immunogenicity: High doses IM more immunogenic than lower doses ID

    • Additional studies planned for better direct comparison of same dose given ID and IM

Source: The WHO Global Influenza Program Surveillance Network

Keeping up with H5N1 Drift: Vaccine Reference Virus Efforts Underway

  • Clade 1 vaccine; trials underway

    • Vaccine candidates: A/VN/1203/2004 and A/VN/1194/2004

  • Clade 2 - subclade 2 candidates available; vaccine production ongoing

    • CDC: Indonesia/05 (Sanofi US; DHHS)

    • NIBSC: A/Turkey/Turkey/1/05

    • St. Jude: A/BHG/Qinghai Lake/1A/2005 and A/WS/Mongolia/244/05

  • Clade 2 - subclade 3 candidates in development

    • CBER/FDA: A/Duck/Laos/3295/06

    • CDC: A/Anhui/1/2005

    • St. Jude: A/Japanese White Eye/HK/1038/06


What Can We Expect of H5N1 Influenza?

  • Since 2003, increasing number of countries in Africa, Asia, and Europe have documented H5N1 virus in poultry or migratory birds.

  • Continued H5N1 evolution, possibly amplified by uncontrolled transmission in high-density poultry.

  • Human cases track exposure to infected poultry and are accelerating in frequency.

    • Clusters and potential human-to-human spread plus epidemic influenza provide continuing chance for reassortment.

Hong Kong model for eliminating infected poultry and preventing human illness

  • Agricultural surveillance and action are critical early steps.

  • Enforcement of market sanitation.

  • Poultry segregation (quail as asymptomatic carriers eliminated).

  • Vaccination with agricultural vaccine (asymptomatic infections possible).

  • Difficult to implement because of social and economic concerns.

Annual Influenza Vaccine Production



~1 rooster for

10 hens






Sheep sera

Millions of





FDA potency


Millions of










FDA approves

supplement to





Filled into vials/



assess growth &

yield of


Formulated lots

Generation of high

yield reassortants





FDA release






? Demand


vaccine use

? Severity of Season

? Recommendations

Influenza Vaccine Production Timeline

U.S. Seasonal Influenza Vaccine: Production and Use

Beyond Eggs and Cell Culture: Research Efforts to Develop New Technologies

Goal: Develop “agile” vaccine platforms

  • DNA

    • Plasmids – single or multiple gene combinations (HA + NP + M2); conserved regions; single subtype or multiple subtypes (H3 + H1 + H5)

  • Vector

    • Adenovirus, alphavirus, salmonella strains

  • Recombinant subunit

    • Expression systems, baculovirus, drosophila

  • Peptide vaccines

    • Synthesized multigenic peptides

  • Vector-based vaccines

Influenza Virus and Protein RNAs: Targets for a “Universal Vaccine”

Source: Subbarao/Murphy

Seasonal Influenza Preparedness

Pandemic Influenza Preparedness

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