Progress Towards a Vaccine for Pandemic Influenza

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					Progress Towards a Vaccine for
     Pandemic Influenza

                     George Risi, MD
                     Missoula, Mt

                   Topics to Review

•   An overview of influenza A virus
•   How vaccines for seasonal influenza are chosen
•   Egg based production methods for seasonal influenza viruses
•   Pandemic influenza. Lessons from previous experiences
•   Highly pathogenic H5N1influenza. How it is different
•   The status of vaccine development for H5N1 influenza
•   Immunologic adjuvants
             Take Home Messages
• Whether it is from H5N1 or some other strain, experts are in
  agreement that another pandemic of influenza will occur.
  Predicting when that will happen is impossible
• There will be a time lag between the beginning of an outbreak
  of pandemic influenza and the availability of an effective
  vaccine. The more that is done now, the shorter that time lag
  will be
• A pandemic of influenza will have significant impacts on
  global health and economy even under the most optimistic of
• The major obstacles to overcome in dealing with pandemic
  influenza include the inability with today’s capacity to meet
  the global demand for vaccine, and the need to provide cross
  coverage between different strains of a pandemic virus
             Overview of Influenza A
• A classic example of a zoonosis
• All influenza A viruses are
  normal inhabitants of the GI tract
  of aquatic and migratory wild
• No illness caused in the natural
• Humans get infected due to
  exposure, either directly or
  through an intermediate host to
  the virus shed by these birds

                              The Virus
• Family Orthomyxoviridae
• Lipid enveloped
• Genome composed of 8 separate                                     (H1-H16)
  fragments of RNA
• Polymerase lacks a proofreading
  function so frequent mutations
• Two major surface proteins
    – Hemagglutinin- binds to host
      cells via sialic acid residues                                  (N1-N9)
    – Neuraminidase- facilitates exit of
      the virus from the host cell
• Other surface proteins are present
  in smaller amounts and elicit less
  host antibody response
                                           Field’s Virology, 5th ed, p 1649
               Transmission Patterns
• Wild aquatic birds are the main
  reservoir for all strains of
  influenza A
• Horses, pigs, domestic poultry,
  whales and seals have been the
  only mammals that are able to be
• Wild aquatic birds, domestic
  poultry and pigs all can transmit
  to humans
• There are stringent strain
  restrictions on a mammalian
  host’s ability to be infected by an
  influenza virus
Permissive Hosts for
Influenza A


 Lancet 2003;362:1733
               HA The Most Immunogenic Surface Protein
                                                        Site B
                 Binding Sites

                         Site A                         Site D

Hemagglutinin             Site E
                          Site C




Wiley DC, Wilson IA, Skehel JJ. Nature. 1981;289:373–378.
Antigenic Drift: Point Mutations
   Lead to Immune Evasion

                  NEJM 2004;350(3):218
28 = 256 possible combinations
   Seasonal (Interpandemic) Influenza
           How Vaccines are Chosen Annually

• Because of antigenic drift and shift, influenza is a constantly changing virus
  which requires global monitoring in order to have a vaccine that matches
  the currently circulating strains.
• Historically only one strain of influenza A has circulated globally at any
  one time.
    – However in 1977 a previously “extinct” virus from the 1950’s was accidentally
      re-released from an unknown storage facility back into the human population
    – Ever since then two different influenza strains have co-circulated globally
• The “one” influenza vaccine that is given annually covers both strains of
  influenza A as well as the dominant strain of influenza B
• Making a trivalent vaccine triples the number of eggs needed and adds
  considerably to the time and complexity of vaccine preparation
     Choice of Virus for the Vaccine
       The WHO Global Influenza Surveillance Network
• Established in 1952, it is a network of 118 National Immunization Centers
  from 89 countries
    – Annually the NIC’s collect over 175,000 samples from patients with influenza
      like illnesses, and submit around 2,000 viruses to the WHO for antigenic and
      genetic analysis
• The viruses are analyzed by one of 4 WHO collaborating centers (US, UK,
  Japan, Australia)
    – By analyzing the dominant strains, WHO along with CDC, CBER, other
      agencies recommend the use of certain strains for the upcoming season, based
      primarily on HA and NA characteristics
• Original isolates are passaged to develop reference strains that are
  distributed to manufacturers to develop seed viruses
• Often the reference strains do not grow well in eggs and thus need to be
  manipulated in some way
• Reassortants are created that utilize the HA and NA from the chosen virus
  with A/Puerto Rico/8/34 (aka PR8), a strain that grows well in
  embryonated chicken eggs
    Egg Based Methods for Making Vaccine
•    Developed in the 1940’s, still the
     dominant method today
•    15% of global egg production is
     devoted to influenza vaccine
•    11 day old fertilized hen’s eggs
     inoculated with live virus, incubated
     at controlled temperature and
•    Virus harvested and inactivated
•    Egg proteins removed
•    Virus disrupted with detergent or
     ether to separate pure H and N from
     the rest
•    Product is purified and then three
     vaccines mixed together into one vial
     for distribution

      Problems with Current Influenza
          Vaccine Manufacturing
• A new product needs to be made each year. Leftover vaccine
  at the end of a season is discarded
• Many variables influence the yield of product
• Supply of raw materials is vulnerable
• Maximum global capacity for influenza vaccine is 900 million
  15 ug doses (yielding only 300 million doses of trivalent
• Number of manufacturers is limited because of low profit
  margins, lack of a guaranteed market, liability claims
• There are significant risks of shortages, delays, and
  mismatches between the vaccine components chosen 6 months
  prior and the circulating strain by the start of influenza season
        Pandemic Influenza: Previous
• Influenza like illness described by Hippocrates in 412 BCE
• Charlemagne’s army 876 CE
• A serious epidemic occurred in Europe in 1173
• First true pandemic probably occurred in 1580
• 10 pandemic influenza events have occurred in the past 300
• Since there are now known to be so many different
  mechanisms responsible for pandemic emergence, the widely
  held conviction among influenza authorities about pandemic
  cyclicity and its scientific rationale has been fading.


There is no predictable periodicity or pattern of major influenza
epidemics. All differ from one another.
Without pandemic cycles, there can be little basis for predicting pandemic
                                           Morens, JID 2007;195:1018
            What Happened in 1918?
• First case attributed to a soldier at
  Camp Funston, Kansas, who had
  been cleaning pig pens
• An existing virus of avian origin
  became genetically adapted to
  attack and transmit between
  humans. The original avian source
  is still unknown
• There were 3 successive waves of
  disease within a 9 month span
• No protection conferred by W1 to
  W2 and 3. Was it even the same
• Mortality rate from W2 and W3
  infections was 2.5% (vs 0.1% for        Camp Funston (now Ft Riley),
  seasonal influenza)                     Kansas, circa 1918
The University of Montana, 1918
Making a bad situation worse…


       Stressful situations
          The “Spanish Flu” of 1918

• Spanish origin a misnomer
• Due to heavy censorship of bad
  news in US and northern Europe
  during the Great War, Spain was
  the first to report it
• Estimates of 50-100 million
  deaths worldwide
• 675,000 Americans were killed
• The average U.S. lifespan
  decreased by 10 years
• Almost 3 times as many people
  were killed by influenza in 6
  months as died in 4 years of
  military action in the Great War
Influenza A Viruses in Humans in the Last Century
              shift             shift
  H1N1                  H2N2        H3N2
  Spanish             Asian     Hong Kong Russian
  Influenza           Influenza Influenza Influenza

                                                           Identical to H1N1 from 1950’s
  1918                  1957            1968            1977
                   H2,N2,PB1     H3,PB1

                                               Influenza A reservoir

                                      l l Tl
                             Tl l T

                                               l Tl l

                                                        16 HA subtypes
                                      Tl l

                                        T               9 NA subtypes
 Highly Pathogenic Avian Influenza
• Why is it of such concern?
• How is it different from
  seasonal influenza?
• How is it different from any
  previous human pandemic
    Highly Pathogenic Avian Influenza,
               H5N1 Type
• There have recently been several outbreaks among poultry of a
  variety of HPAI subtypes, with limited spread to heavily
  exposed humans
   –   H9N2
   –   H7N7
   –   H7N3
   –   H5N1
• Only strains of influenza having H1,2,3 or N1,2 have been
  able to establish stable lineages in humans
• Human infections by other strains have long been recognized.
  While individuals may suffer severe disease, there is usually
  limited impact on the population at large
• This is because receptor specificity has provided a “species
       Specificity of the HA Binding Site

Alpha 2,3 binding of sialic
Acid to galactose. Avian strains

                                            Alpha 2,6 binding:
                                            Human strains

                                   H5N1 may be able to mutate to bind
                                    to 2,6 linked sites
                                   Recently, 2,3 connections have been
                                    found in distal human airways
     Hemagglutinin Precursor HA0
• HA0 precursor protein must
  be cleaved into HA1 and
  HA2 molecules in order to
  efficiently fuse with the host
  endosomal membrane
• A “normal” HA precursor
  can only be cleaved by
  trypsin-like proteases that
  are present only in the
  respiratory and
  gastrointestinal tracts
• All HPAI strains have the
  same type of mutation
   The Influenza H5 Hemagglutinin Gene
                    HA1                                       HA2

  Avirulent                                   ….RETR*GLF

  HPAI isolates                               ….RKKR*GLF

  1997 HK human isolates                …RERRRKKR*GLF

  2003 HK human isolates                …RERRRKKR*GLF
When multiple basic amino acids are introduced adjacent to the
cleavage site, the HA0 precursor becomes cleavable by a wide range
of proteases that have ubiquitous tissue distribution. So virus is able
to invade multiple organs including brain, and very high levels of
virus are found in birds organs
• Compared to previous HPAI strains, it is more widespread and more
  virulent, even for aquatic birds
    – First detected in Guangdong province in 1996, fatal to geese. Little attention
      paid until humans infected in Hong Kong, 1997. 18 infected, 6 deaths
    – Culling of all poultry (1.5 million birds) in Hong Kong ended the first wave of
      virus, but it continued to circulate among apparently healthy ducks in the
      coastal provinces of China
• From 2000 onwards a series of H5N1 reassortants were detected in ducks,
  chickens etc. By 2003 a dominant strain (the Z strain) had emerged which
  was sporadically lethal for waterfowl but 100% lethal for chicken, turkey,
• Z strain has been able to jump the species barrier to cats, dogs, humans, and
  several other mammals
• First human infections from Z strain occurred in 2003
• The Z strain has developed several distinct variants (Clades)
H5N1 Influenza: Global Spread

                 Webster, NEJM 2006;355:2174
  Will H5N1 Cause the Next Pandemic?

• Global spread with unprecedented rapidity
• High virulence for multiple types of birds
• Never before seen ability to infect and kill several
  unique mammalian species
• Several variants have been described that have
  increased affinity for the human alpha 2,6 sialic acid
  receptor site, but none yet have completed the jump
  to easy transmission
• Will that final step occur or not? What if we guess
   Consequences (US only) of a Severe
         Influenza Pandemic
• 200 million infected, 90 million clinically ill, 2
  million fatalities
• 30% of all workers ill, of whom 2.5% would die
• Those workers would miss a mean of 3 weeks of
  work resulting in a reduction of the gross domestic
  product of 5%
• 18-45 million people would require outpatient care
• Economic costs would total around $675 billion
• Thus there is an urgent need for a vaccine (among
  other things)
                         Source: Congressional Budget Office
     Elements of Pandemic Preparedness

• Virologic and disease surveillance in humans and animals
   – WHO global network for human influenza
   – WHO animal influenza network
• Plan for stockpiling and rational use of antiviral agents
   – Antineuraminidase drugs (Oseltamivir, Zanamivir)
   – Adamantanes (Rimantadine, Amantadine)
   – Combinations
• Vaccines: library of high-yield reassortant viruses, improve production
  methods, allocation and distribution, alternative substrates
   – Six months to prepare
• Emergency plans to deal with community disruption and increased
  demand for medical services
       Status of Vaccine Development
• 2006 WHO launched the Global Pandemic Influenza Action
  Plan. US $10 billion committed over 10 years
• Currently 16 vaccine manufacturers from 10 countries are
  developing prototype vaccines
   – At present over 40 trials completed or ongoing
• Methods being explored
   – Killed split virus (modeled after seasonal vaccine methods)
   – Same with an immunologic adjuvant
   – Cold adapted live attenuated virus (akin to Flumist)
   – Components expressed in nonhuman viral vectors (baculovirus,
     canarypox, etc)
   – Purified DNA based vaccine
   – Universal vaccine against a conserved epitope. The holy grail
Generation of a Candidate
Pandemic Influenza Vaccine Strain

                           Katz, ASM News 2004;70(9):412
       Traditional Egg Based Trial
• A vaccine for Clade 1 Influenza A H5N1 virus
  (A/Vietnam/1203/2004[H5N1]) was developed using reverse
  genetics, with only HA and NA expressed
• Doses given were 7.5, 15, 45 and 90 ug. Two doses 28 days
• Only ½ of those who received the 90 ug dose developed an
  acceptable antibody response
• With current global capacity of 900 million doses of 15 ug
  vaccine, only 75 million persons could be immunized with this
  vaccine and only half of them would be protected
• This vaccine does not appear to confer cross clade protection

                                  Treanor, NEJM 2006;354:1343-51
             Immunologic Adjuvants
• Agents incorporated into vaccine formulations to enhance the
  immunogenicity of the antigen
• Three basic mechanisms
   – Affect antigen delivery and presentation
   – Induce immunomodulatory cytokines
   – Effects on antigen presenting cells
• Used in several standard vaccines
   –   Hepatitis A & B
   –   DTaP
   –   HiB
   –   Prevnar
   –   Some influenza vaccines licensed in Europe
The M2 complex is highly conserved
but normally elicits minimal immune
recognition from the host
     Pandemic Preparedness Issues
• Capacity. Current global capacity is 900 million
  doses of a 15 ug vaccine.
   – Urgent need to increase capacity
   – Antigen sparing techniques being investigated
• Limitations of egg based technology
   – HPAI’s are lethal to eggs. Thus extensive manipulation
     necessary to make a seed virus that can be grown
   – Limit to the number of eggs that can be produced even now
   – If HPAI strikes globally there will be fewer chickens to lay
• Development of technologies that don’t need eggs
  Conclusions: Pandemic Influenza
• Not if but when, a pandemic will occur
• H5N1 is the most ominous current threat but others
  may emerge
• Vaccination can blunt the impact if
   – Cross clade pre-pandemic vaccines can be made and
     stockpiled in advance
   – Production methodology improves allowing more vaccine
     to be made
• A pandemic will cause global disruption even under
  the most optimistic scenarios

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