Rising to the Challenge: An Analysis of the Influenza .../media/Informa-Shop-Wind… · The swine...

Rising to the Challenge: An Analysis of the Influenza Vaccine Landscape in Response to the Swine Flu Pandemic

CitelinePharma intelligence |

Gabrielle GessnerAssociate Director, Infectious& Genitourinary Diseases

Sean McDonnellDrug Analyst II


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Influenza viral outbreaks occur annually around the world, with some tropical regions experiencing year round viral circulation (WHO, 2013). Influenza viruses change, or drift, constantly, leading to different virus strains circulating each flu season or sometimes within a single season (CDC, 2013). Worldwide, these annual epidemics result in approximately three to five million cases of severe illness each year, and about 250,000 to 500,000 deaths (WHO, 2013).

The swine influenza pandemic in 2009/10 highlighted numerous challenges in providing effective influenza vaccine coverage. These include the long lag time between flu virus selection by government agencies and actual shipment of vaccine, resulting in possible mismatch of vaccine strains; the lack of production capacity; and the reluctance of some individuals to get vaccinated due to intramuscular administration or exclusionary conditions (ex. egg allergy).

This paper evaluates the methods manufacturers pursued in response to the swine flu pandemic, with an analysis of alternate manufacturing methods and routes of administration. We analyzed the clinical landscape of influenza vaccines since 2010, including approved vaccines and trial metrics, to identify how manufacturers addressed these issues and how effective they have been. Have the major players in influenza vaccines shifted? Are trial timelines or other characteristics different? With the recent emergence of novel viruses such as the MERS coronavirus, flexible vaccine production and short development timelines become even more vital in addressing future pandemics.


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addressing the challenges in influenza Vaccine ProductionManufacturers investigated various strategies since 2009 to address the challenges associated with

effective influenza vaccination. Traditionally, influenza vaccines have been produced in chicken eggs which

requires a long production time, so the vaccine strains have to be chosen 7-8 months prior to vaccine delivery.

Since the circulating influenza strains are not known this far in advance, virus strains that are not a close

match to the strains that actually circulate during the upcoming flu season may be selected, resulting in

reduced vaccine efficacy against clinical infection. Other issues associated with effective influenza vaccination

include limited vaccine supplies or patient preferences. As such, manufacturers explored ways to counteract

these obstacles by shortening vaccine production time via alternate manufacturing methods, adding

additional virus strains into the vaccine, and developing alternate routes of administration.

alternate Manufacturing Methods

Using cell culture techniques in the manufacturing process of influenza vaccines is one way to vastly reduce

the vaccine production time, primarily by eliminating the long lead time needed to grow the vaccine seed

virus in chicken eggs. This gives manufacturers the ability to provide additional vaccine supplies during a

season if needed or manufacture a new strain quickly in the event of a pandemic. Cell culture also offers

higher purity and provides a larger initial production volume than traditional egg-based processes. In

addition, cell culture eliminates any possibility of residual egg proteins remaining in the vaccine, making

the vaccine safe for individuals with an egg allergy.

In total, 38 cell culture vaccines were developed targeting influenza since the early 1990s (Figure 1).

Seasonal vaccines make up 37% (14) of these; however, the majority have been developed for specific

monovalent vaccines.

Source: Pipeline®, August 2013 Citeline

Figure 1. Cell Cultured Influenza Vaccines By Strain

H3N2, (1)

H5N1, (12)

H7N9, (1)

H9N2, (1)

H1N1, (6)

Pandemic(Unspecified),

(3)

Seasonal, (14)


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Figure 2. Companies Developing Cell Culture Manufactured Influnza Vaccines

0 1 2 3 4 5 6 7 Vivaldi Biosciences

UMN Pharma Takeda

SK Holdings Sanofi

Protein Sciences Polymun Petrovax Novavax Novartis

Non-industrial source Merck & Co

Medigen Biotechnology LG Life Sciences

Kaketsuken Johnson & Johnson

GlaxoSmithKline GE Healthcare Daiichi Sankyo

Cadila BioDiem

Bharat Biotech Baxter International

AstraZeneca Astellas

ADImmune Abbott

Number of Influenza Vaccines

Dev

elop

ing

Com

pan

y

Cell culture (unspecified)

EB66 duck cell

Insect (baculovirus)

Mammalian (unspecified)

MDCK

Vero

Of the 38 cell culture vaccines in development, 27 different companies have been involved (including

licensees) (Figure 2, Table 1). The clear leader in this field is Baxter, who invested in 6 separate Vero cell

culture vaccines, of which 3 have been successfully launched (PreFluCel, Celvapan H1N1 & Celvapan

H5N1). Novartis is also well established in this area with 5 vaccines, including their Phase II MDCK cell-based

H5N1 product. Rounding out the Top 3 is GlaxoSmithKline (GSK), developing 4 alternatives to traditional

egg-based methods.


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table 1. cell-cultured influenza Vaccines

Drug name Global status originator licensee Manufacturing influenza type

Flucelvax Launched NovartisMammalian (unspecified)

Seasonal

PreFluCel LaunchedBaxter International

Vero Seasonal

Celvapan, H5N1 LaunchedBaxter International

Vero H5N1

Celltura Launched NovartisCell culture (unspecified)

Pandemic (H1N1)

HN-VAC LaunchedBharat Biotech


Pandemic (H1N1)

Celvapan, H1N1 LaunchedBaxter International

VeroPandemic (H1N1)

MonoGrippol Neo Launched PetrovaxAbbVieAbbott


Pandemic (H1N1)

live attenuated influenza vaccine, BioDiem/Nobilon

Launched BioDiem Merck & Co Cell culture (unspecified) Seasonal

Influvac TC Registered Abbott AbbVie MDCK Seasonal

Flublok RegisteredProtein Sciences

AstellasUMN Pharma


Seasonal

Vapacel Registered TakedaBaxter International

Vero H5N1

influenza, H5N1, cell culture, Kitasato Daiichi Sankyo

Pre- registration

Daiichi SankyoCell culture (unspecified)

H5N1

influenza vaccine, PER.C6 Inflexal V, Crucell

Phase IIJohnson & Johnson


Seasonal

trivalent influenza vaccine (H3N2/H1N1/B), Novavax

Phase II Novavax

CadilaGE Health-careLG Life Sciences


Seasonal

H5N1 pre-pandemic influenza vaccine, cell culture, Novartis

Phase II Novartis MDCK H5N1

VLP vaccine, influenza H5N1, Novavax

Phase II Novavax

Bharat BiotechLG Life Sciences


H5N1

Panblok Phase IIProtein Sciences

UMN PharmaAstellasSanofi


H5N1

Vero-Vac Phase I Polymun Vero Seasonal


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AT-301 Phase IMedigen Biotechnology

MDCK H5N1

H3N2c vaccine, Novartis Phase I NovartisCell culture (unspecified)

H3N2

H5N1 LAIV influenza vaccine, BioDiem

Phase I BioDiem Merck & CoCell culture (unspecified)

H5N1

H5N1 influenza vaccine, Baxter/DynPort

Phase IBaxter International

Vero H5N1

UMN-0901 Preclinical UMN PharmaInsect (baculovirus)

H9N2

H7N9 influenza vaccine, Novartis

Preclinical NovartisCell culture (unspecified)

H7N9

influenza vaccine, GSK, seasonal, cell culture

PreclinicalGlaxoSmith-Kline

KaketsukenEB66 duck cell

Seasonal

influenza vaccine, cell-culture, SK Chemicals

Preclinical SK HoldingsCell culture (unspecified)

Pandemic (Unspecified)

FluCell quadrivalent PreclinicalJohnson & Johnson

Cell Culture Seasonal

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Initially developed targeting avian influenza strains, the cell culture vaccines have exploded onto the

influenza landscape in response to the swine flu pandemic. These vaccines have addressed multiple

challenges of influenza vaccines, shortening production timelines and opening the market to additional

populations, such as those with egg allergies.

Quadrivalent Vaccines

The other method used to combat the strain drift of influenza added an additional strain to the existing

approved seasonal influenza vaccines, producing quadrivalent instead of trivalent vaccines. A number of

sponsors pursued this method with successful results.

Traditional seasonal influenza vaccines consist of the two main influenza type A strains and one influenza type

B strain. However, the 2013/14 season is the first where we will see the availability of several quadrivalent

vaccines, which contain an additional B strain. There are currently 4 quadrivalent vaccines approved for use

in the upcoming 2013-14 influenza season, with a further 5 vaccines advancing through the pipeline (Table 2).

table 1. cell-cultured influenza Vaccines (continued)

Drug name Global status originator licensee Manufacturing influenza type



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AstraZeneca’s (MedImmune’s) quadrivalent formulation of FluMist was the first quadrivalent influenza

vaccine to be approved worldwide (February 2012 in the US), and is also the only quadrivalent vaccine

available that is administered intranasally. It is currently awaiting EU approval from the EMA.

GSK’s quadrivalent Fluarix vaccine was the next to be approved in the US in December 2012. It is crucially

also approved in the UK (as Fluarix Tetra) and Germany (as Influsplit Tetra), and is currently awaiting further

regulatory rulings in Australia, Switzerland, and Taiwan. Being the only quadrivalent influenza vaccine

currently available outside of the US should give GSK a huge untapped market for the 2013/14 influenza

season, which will no doubt be reflected in their sales revenue for the 4th quarter of 2013.

Sanofi’s quadrivalent Fluzone formulation was approved in the US in June 2013. While arriving later to

an already crowded field, Sanofi has a major advantage over both AstraZeneca (MedImmune) and GSK

in that Fluzone quadrivalent is approved for infants as young as 6 months old, which is a full 18 months

earlier than FluMist quadrivalent and 30 months earlier than Fluarix quadrivalent. This gives Sanofi

complete exclusivity on all quadrivalent vaccine inoculations of infants and toddlers aged 6 months to

2 years of age in the US, a particularly vulnerable population for influenza infection.

The 4th and final quadrivalent vaccine approved in time for the 2013/14 influenza season is GSK’s second

quadrivalent influenza vaccine, FluLaval quadrivalent, which was approved in the US in August 2013. While

currently approved, GSK concedes that only a limited amount of FluLaval quadrivalent will be available in

2013. However, from 2014 onward, GSK should have the capacity to supply Flulaval quadrivalent to the US

from its manufacturing plant in Quebec, Canada and will also continue to manufacture Fluarix quadrivalent

from its facilities in Dresden, Germany and Pennsylvania, US.

table 2. Quadrivalent influenza Vaccines

Drug name Global status originator licensee Manufacturing Delivery route

FluMist quadrivalent LaunchedMedImmune (AstraZeneca)

Egg-based Inhaled, transnasal

Fluarix quadrivalent Launched GlaxoSmithKline Egg-basedInjectable, intramuscular

Fluzone quadrivalent vaccine, Sanofi

Launched Sanofi Egg-based

Injectable, intradermalInjectable, intramuscular

FluLaval quadrivalent Registered GlaxoSmithKline Egg-basedInjectable, intramuscular

influenza vaccine, Vaxigrip quadrivalent, Sanofi

Pre- registration

Sanofi Egg-basedInjectable, intramuscular

quadrivalent VLP seasonal flu vaccine, Novavax

Phase II NovavaxLG Life Sciences

Egg-basedInjectable, intramuscular

influenza vaccine, quadrivalent (MF59-adj), Novartis

Phase II Novartis Egg-basedInjectable, intramuscular

seasonal influenza vaccine, quadrivalent, Medicago

Phase I Medicago Plant based Unspecified

FluCell quadrivalent PreclinicalJohnson & Johnson

Cell CultureInjectable, intramuscular


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Figure 3. Quadrivalent Vaccine Trials by Phase

0

2

4

6

8

10

12

AstraZeneca GSK Medicago Novartis Novavax Sanofi

Sponsor

Num

ber

of

Tria

ls

Trial Phase

IV

III

II/III

II

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current landscape in Quadrivalent Vaccine Development

Not surprising given their double threat in approved quadrivalent vaccines, GSK has conducted the

highest number of trials using quadrivalent influenza vaccines at 10 trials, followed by Sanofi with 8 trials

(Figures 3, 4). Almost all of GSK’s (9 out of 10 trials) and Sanofi’s (7 out of 8 trials) trials were in Phase III,

while AstraZeneca (MedImmune) is the only sponsor conducting Phase IV trials using their FluMist

quadrivalent vaccine, as of August 2013. Sanofi has the largest number of ongoing (planned, open, or

closed) quadrivalent vaccine trials (3 out of 8). Of note, there are no Phase I trials for quadrivalent vaccines,

primarily because this first crop were based on trivalent vaccines to speed development.

Source: Trialtrove®, August 2013 Citeline


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The other three sponsors testing quadrivalent vaccines in the clinic are Novartis, Novavax, and Medicago

(Figures 4, 5). Novavax is developing their quadrivalent vaccine for pediatric, adult, and elderly populations.

Notably, CSL decided not to pursue a quadrivalent vaccine, despite being a major player in trivalent

seasonal influenza vaccines.

Sponsor

0

2

4

6

8

10

12

AstraZeneca GSK Medicago Novartis Novavax Sanofi

Figure 4. Quadrivalent Vaccine Trials by Status

Num

ber

of

Tria

ls

Trial Status

Terminated

Planned

Open

Completed

Closed



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With both quadrivalent and trivalent vaccines currently available to the public, it remains to be seen if

quadrivalent manufacturers will continue to produce their trivalent vaccines after the 2013/14 influenza

season. Provided there are no surprises during this transition season, the trivalent vaccines may eventually

be phased out in markets where the quadrivalent vaccine is approved.

alternate routes of administration

Various sponsors sought alternate routes of administration to address supply issues and tap into increased

patient preference and/or additional populations. Traditional influenza vaccines are administered intramuscularly

or intranasally. Intradermal (ID) and subcutaneous (SC) administrations have been pursued as dose-sparing

methods since they require less volume to administer. These routes of administration may also be preferable

to some subjects who aren’t eligible for the live intranasal vaccine since they use a smaller needle and don’t

require placement into the muscle tissue. However, intradermal and subcutaneous administration can be more

difficult for health providers to provide consistently without additional training. Additionally, since the intranasal

vaccine is a live viral vaccine, it is contraindicated for people with asthma or respiratory issues. As such, another

route of administration would provide an alternate to intramuscular vaccines for people with these conditions.


Figure 5. Current Landscape for Quadrivalent Vaccines


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0

5

10

15

20

25

30

AbbVie

Astella

s Pha

rma;

UMN P

harm

aBax

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CLL P

harm

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CSL Lt

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Daiich

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Denka

Seike

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Echo Th

erap

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GSK

Inovio

Pha

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John

son &

John

son

Kaket

suke

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Med

icago

Novarti

s

Pfizer

Sano

fi

Sano

fi Pas

teur

MSD

SEEK

Valne

va

VaxIn

nate

Figure 6. Intradermal and Subcutaneous Influenza Vaccine Trials

SC

ID & SC

ID

Route of Administration

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Sanofi is followed by Inovio Pharmaceuticals and Novartis with 4 trials each. Inovio is also focusing on intradermal

administration, while Novartis is pursuing both intradermal and subcutaneous formulations. In subcutaneous

formulations, Novartis, VaxInnate and CSL are all active in the clinic with 3 trials each (Figures 7, 8).

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5

10

15

20

25

30

CLL P

harm

a

Daiich

i San

kyo

Echo Th

erap

eutic

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GSK

Inovio

Pha

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als

John

son &

John

son

Med

icago

Novarti

s

Pfizer

Sano

fi

Sano

fi Pas

teur

MSD

Valne

va

VaxIn

nate

Figure 7. Intradermal Vaccine Trials by Phase

IV

III

II

I/II

I

Trial Phase

Sanofi (Sanofi and Sanofi Pasteur MSD) is by far the leader in evaluating vaccines with alternate routes of

administration, with 85% more trials than their nearest competitors (Figure 6). This isn’t surprising considering

they have the only approved intradermal formulation with Fluzone intradermal.


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changes in the influenza Vaccine landscapeTo understand any changes that occurred in the influenza vaccine competitive landscape as a result of the

2009/10 swine flu pandemic, we compared a number of areas before and after January 2010, including

vaccine approvals, sponsors, and trial metrics.

changes in approved influenza Vaccines

The 2009/10 influenza virus pandemic placed government agencies worldwide under enormous pressure

to act swiftly and decisively due to intensified media coverage. One outcome of this was that manufacturers

were encouraged to develop monovalent vaccines against the new H1N1 strain with the promise of

expedited regulatory approval.

September 2009 saw the initial wave of these H1N1 vaccine approvals (7 in total) as the 2009/10 influenza

season began in earnest in the Northern Hemisphere (Figure 9, Table 3). Two vaccines were approved quickly

in the EU: GSK’s Pandemrix H1N1 and Novartis’ Focetria H1N1. Both vaccines were initially authorized

under ‘exceptional circumstances’ by the EMA due to the high medical need, despite a lack of clinical

information. This limited approval was eventually lifted in August 2010 after both companies were able

to supply the necessary clinical data. Similarly, the US also approved 4 H1N1 vaccines in September 2009,

manufactured by Sanofi, CSL, Novartis and AstraZeneca (MedImmune).


0

0.5

1

1.5

2

2.5

3

3.5

AbbVie

Astella

s Pha

rma;

UMN P

harm

aBax

ter

CSL Lt

d

Denka

Seike

n

Kaket

suke

n

Novarti

s

Sano

fi

SEEK

VaxIn

nate

Figure 8. Subcutaneous Vaccine Trials by Phase

IV

III

II/III

II

I/III

Trial Phase


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October 2009 saw another 5 first-time approvals for monovalent H1N1 vaccines. Baxter’s Celvapan H1N1,

the only approval that month in the EU, made history by becoming the first cell culture influenza vaccine

approved. Green Cross, Microgen and GSK also gained premier approvals for vaccines during October

2009 in South Korea, Russia and Canada, respectively. The number of new approvals trailed off considerably

after October, with only 4 new vaccines coming to market in 2009, including Novartis’ Celtura and Petrovac’s

MonoGrippol Neo cell culture products. In 2010, a further 5 H1N1 vaccines were approved by regulatory

agencies, 4 in India and 1 in Taiwan.

Sep-09 Oct-09 Nov-09 Dec-09 May-10 Jul-10 Aug-10 Sep-10 Oct-10

ADImmune 0 0 0 0 0 0 0 1 0

AstraZeneca 1 0 0 0 0 0 0 0 0

Baxter International 0 1 0 0 0 0 0 0 0

Bharat Biotech 0 0 0 0 0 0 0 0 1

BioDiem 0 0 0 0 0 1 0 0 0

CSL 1 0 0 0 0 0 0 0 0

GlaxoSmithKline 1 1 0 0 0 0 0 0 0

Green Cross 0 1 0 1 0 0 0 0 0

Microgen 0 2 0 0 0 0 0 0 0

Novartis 2 0 1 0 0 0 0 0 0

Petrovax 0 0 0 2 0 0 0 0 0

Sanofi 1 0 0 0 0 0 0 0 0

Serum Institute of India 0 0 0 0 0 0 1 0 0

Sinovac Biotech 1 0 0 0 0 0 0 0 0

Zydus Cadila 0 0 0 0 1 0 0 0 0

0

1

2

3

4

5

6

7

8

No.

of A

pp

rove

d H

1N1

Vacc

ines

By

Mon

th

Figure 9. Timeline Of H1N1 Vaccine First Approvals By Originator


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changes in trial landscape

There were some shifts seen in the major players in influenza vaccine development after the 2009/10

pandemic (Figures 10, 11). GSK, Sanofi, and Novartis remained the top three sponsors of influenza vaccine

trials both before and after January 2010. However, AstraZeneca (Medimmune), Pfizer, and AbbVie

dropped off the Top 10 sponsors after January 2010, indicating their shift in focus away from influenza

vaccine development. Baxter and CSL remained in the Top 10, with the entrance of Johnson & Johnson,

Serum Institutes of India, AdImmune, and Novavax to round out the Top 10 after January 2010.


table 3. H1n1 influenza Vaccines approved Worldwide since 2009/10 Pandemic

Vaccine name originator licenseeDate of 1st approval

region of first approval

Panflu.1 Sinovac Biotech Boryung Sep-09 China

Pandemrix H1N1 GlaxoSmithKline Sep-09 EU

Panenza Sanofi Sep-09 US

Panvax H1N1 CSL Sep-09 US

Focetria H1N1 Novartis Sep-09 EU

Fluvirin H1N1 Novartis Sep-09 US

Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal

AstraZeneca Sep-09 US

Celvapan, H1N1 Baxter International Oct-09 EU

Green Flu-S Green Cross Oct-09 South Korea

Influvir Microgen Oct-09 Russia

Pandeflu Microgen Oct-09 Russia

Arepanrix GlaxoSmithKline Oct-09 Canada

Celtura Novartis Nov-09 Germany

Green Flu-S Plus Green Cross Dec-09 South Korea

MonoGrippol Neo Petrovax AbbVie Dec-09 Russia

MonoGrippol Plus Petrovax Dec-09 Russia

VaxiFlu-S Zydus Cadila May-10 India

NasoVac BioDiem

Serum Institute of IndiaMerck & CoChangchun BCHT Biotechnology

Jul-10 India

EnzavacSerum Institute of India

Aug-10 India

AdimFlu-S ADImmune Sep-10 Taiwan

HNVAC Bharat Biotech Oct-10 India


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0 50 100 150 200 250

GSK

Novartis

Sanofi

AstraZeneca

Medimmune

Pfizer

CSL

Baxter

AbbVie

Sinovac Biotech

Figure 10. Top 10 Industry Sponsors of Influenza Vaccine Trials Prior to January 2010

avian/pandemic

seasonal

swine/pandemic

Vaccine Type

Number of Trials


Figure 11. Top 10 Industry Sponsors of Influenza Vaccine Trials After January 2010

0 50 100 150 200 250

GSK

Novartis

Sanofi

Johnson & Johnson

ADImmune

Baxter

Novavax

Sanofi Pasteur MSD

Serum Institute of India

CSL avian/pandemic

seasonal

swine/pandemic

Number of Trials

Vaccine Type


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0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

Seas

onal

Swine

Avian

Seas

onal, S

wine

Seas

onal, A

vian

Figure 12. Influenza Vaccine Trial Metrics [Prior to January 2010]

Avg Countries per Trial

Avg Reported Sites per Trial Avg Predicted Max Enroll Period per Trial (months)

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Source: Trialtrove®, Trialpredict®, August 2013 Citeline

Looking at the comparison between trial metrics before and after January 2010, there does not seem

to be much of a change in the countries per trial or average sites per trial (Figures 12, 13). However, while

the average predicted maximum enrollment rate per trial remained the same for most types of vaccines,

there was a significant increase in the average enrollment rate for seasonal and avian vaccine combination

trials. This could reflect decreased volunteer interest in avian influenza vaccine trials following the swine

influenza pandemic.


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Source: Trialtrove®, Trialpredict®, August 2013 Citeline

During the 2009/10 swine flu pandemic, manufacturers swiftly responded to the public health crisis with

additional influenza vaccine approvals in a very short timeframe. The leaders in influenza vaccines solidified

their presence in this area, with the emergence of some new companies in this area as well.

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

Seas

onal

Swine

Avian

Seas

onal, S

wine

Seas

onal, A

vian

Figure 13. Influenza Vaccine Trial Metrics [After January 2010]

Avg Countries per Trial

Avg Reported Sites per Trial Avg Predicted Max Enroll Period per Trial (months)


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conclusionThe 2009/10 H1N1 influenza pandemic caused a shift in the traditional focus and processes surrounding

influenza vaccine production. Manufacturers rose to the challenge posed by the pandemic and explored

additional options to increase flexibility in influenza vaccine production. This resulted in even greater

innovation and multiple strategies that improved manufacturing processes as well as offering multiple

vaccine types, both of which were successful in addressing this serious public health challenge.

With the emergence of the H7N9 influenza strain in Asia during the spring of 2013, these methods will

be essential in facing new influenza pandemics, and applicable to other viral pandemics that may emerge.

Will manufacturers who focused on one strategy, like GSK’s two quadrivalent vaccines approved in multiple

markets, come out on top? Or will it be the manufacturers that focused on multiple strategies like Sanofi

with a quadrivalent vaccine (Fluzone QIV) in additional populations (infants and toddlers), an intradermal

vaccine (Fluzone ID), and a high-dose vaccine for the elderly (Fluzone HD)? The upcoming Northern Hemis-

phere influenza season will be followed with great interest as we see the answers to these questions play out.

referencesCDC, 2013, http://www.cdc.gov/flu/about/season/flu-season-2013-2014.htm WHO, 2013, http://www.who.int/mediacentre/factsheets/fs211/en/index.html


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