Livestock vaccines: Development and market access presentation by Jean de Foucauld, Ceva Santé Animale, Libourne, France

1. Livestock vaccines: development and
market access
FAO symposium: The Role of Agricultural Biotechnologies in Sustainable Food Systems and Nutrition
Session: Facing the challenges of climate change: Adaptation in the livestock and fishery sectors
Speaker: Jean de Foucauld, Senior Biology Expert, Ceva Santé Animale
speaking on behalf of HealthforAnimals
Rome, February 2016

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80+% global animal health sector
In addition, 29 regional/national associations
represent 100+ smaller/medium-sized
companies.
About HealthforAnimals
• global representative body companies/associations
• R&D, manufacturing and commercialisation
• veterinary medicines, vaccines + other animal health products
Animal health companies provide value to society:
• by protecting animals and humans from diseases
• keeping pets and food-producing animals healthy
• public health benefits we bring include:
• safer and more secure food supplies
• more efficient production for increased food supply
• improved reactivity and sustainability
• prevention of the transmission of zoonotic diseases
HealthforAnimals Top 10 global companies

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• Climate change along with other factors like increased movement of people
and animals, triggers new and fast moving livestock disease patterns
• Almost every day we learn of news related to this (the Philippines very recently
with Newcastle disease in poultry)
• Vaccines who are essential of almost all livestock breeding systems are
already available to fight some of these diseases but new vaccines are also
needed
• Gene technology introduced some 30 years ago has allowed developing
vaccines that are already saving millions of livestock and new innovative
solutions are ready in the laboratory
• Delivering new solutions to all customers starts with the science but much
more is needed and this makes the whole difference!
Introduction and setting the scene

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• Of 25 major human diseases, 17 are zoonoses (underligned)
• Of 1500 human infectious diseases, about 65% zoonotic
• One new disease emerges every 7 months
Climate change – zoonotic diseases
Malaria
Cholera
Influenza
Diarrhoea
Filiariasis
Int. Nematodes
Sleeping sickness
Chagas
West Nile
Yellow Fever
Lyme disease
Meningococcal
meningitis
Leishmaniasis
Dengue
Japanese encephalitis
St Louis encephalitis
Rift Valley Fever
Ross River Fever
Murray Valley Fever
Schistosomiasis
STDs
Trachoma
Tuberculosis
River blindness
Childhood disease
High climate sensitivity
Source: International Livestock Reseach Institute: Climate Change and Zoonoses Adaptation and Mitigation

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• African swine fever (ASF): African disease threatens global $150 billion/year pig
industry
• Contagious bovine pleuropneumonia (CBPP): regional losses to CBPP amount to ~
$60 million/year
• East Coast fever (ECF) : regional losses exceed $300 million/year; kills ~ 1million
cattle/year
• Rift Valley Fever (RVF): small ruminants, cattle and human. 2006/7 outbreak Kenya
cost ~ $30 million, 309 human cases in Kenya, Somalia and Tanzania; 140 deaths
• Trypanosomosis: ruminants and for some species humans; affecting YYY
Vaccines availability for these diseases:
• ASF – no vaccine
• CBPP – duration of immunity is short lived and vaccine can cause side reactions
• ECF – live vaccine difficult to manufacture, needs liquid nitrogen cold chain and
oxytetracycline co-treatment - costs 8~12 $/dose
• RVF – vaccine can cause abortions in sheep; human vaccine not available
• Trypanosomosis: no vaccine
Source: International Livestock Reseach Institute: Climate Change and Zoonoses Adaptation and Mitigation
Research is still needed

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www.healthforanimals.org
• There are three pillars to bring vaccine innovation to livestock in a timely
manner
• A good scientific demonstration of a vaccine solution
• A proper vaccine development (up to the capacity to produce and get the
marketing authorisations in the target countries)
• The right access to the market
• In addition we may need: DIVA system, protection of newborns, gestating
animals, wildlife, single vaccination, reduction of transmission, eradication,
establishment of vaccine banks for rapid deployment?
• Looking at science, there are a few examples of new technologies that have
already, or will help, fighting livestock diseases (if put on the market)
• Let us discuss some of them: avian influenza H5 vaccine, HVT and Pox
platforms and non-replicative ‘replicon’ technology (used for RVF candidate
vaccine).
What is needed to access customers ?

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• It is a major disease of poultry: H9, H7 and H5
• Can become highly virulent (H5&7)
• Can become a zoonosis with two situations
• The humans being infected by poultry but not able to transmit the disease
• The virus becomes contagious between humans, not needing anymore
the poultry host
• The main difficulties to fight the disease are:
• Reducing the contagion, by reducing circulation of the virus
• Meaning reducing excretion from infected birds (not only the symptoms)
• Mass vaccination as early as possible (in presence of maternal
antibodies)
Avian Influenza example

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Goal of AI vaccines
1 – Infection
3 – Re-excretion
2 - Clinical expression
HIGHER RESISTANCE
TO INFECTION
REDUCTION OF RE-EXCRETION
CLINICAL PROTECTION
+
+

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• No conventional vaccine could do this
• This is possible with a vector vaccine (Vectormune® AI)
• A vector platform: HVT
• A avian influenza targeted gene: H5 (Europe 2006)
• Vaccine tested in different conditions:
• Different challenge strains from very different parts of the world (see later)
• Different bird categories including for very long duration of immunity
• With maternal antibodies
• Registered in the USA (vaccine bank)
• Registered in different countries where authorities have decided to vaccinate
• First results very encouraging ; for this market access is key and in this case,
access to the hatcheries
Avian Influenza example

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H5N1
AIV
HA
HA gene
AIV genome
HVT
Non essential
gene
HVT = Vector
HVT
Insertion site
AIV = Donor
FC 126 strain
A/swan/Hungary/4999/2006
(H5N1 clade 2 – subclade 2 AIV strain)
Inserted modified
HA gene
« insert »

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Protection ≥ 80%
Significant
reduction of shedding
Cross clade
efficacy
of
Vectormune® AI
HA insert

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Protection ≥ 80%
Significant
reduction of shedding
Cross clade
efficacy
of
Vectormune® AI
Vietnam 2004
Mongolia 2005
Egypt 2008
Indonesia 2007
Bangladesh 2011
Hungary 2006
Egypt 2010
Indonesia 2010
Egypt 2008
Egypt 2011
Germany 2014

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• What is next for HVT-AI?
• Improve market access for AI vaccination in hatcheries: registration,
government policies, marketing…
• Update the inserted gene
• HVT as platform for poultry disease vaccines
• Well known, very safe for the target species and environment
• Works in presence of maternal antibodies and provides long duration of
immunity
• Used in different registered vaccines (7 different constructs registered)
• Tens of billion doses used in many different countries of the world
• In the case of AI: updating the construct with newest AI serotype and
clade is fast and easy (using the same genetic engineering technology)
• Should avoid going through the full development & registration processes
(see later discussion on this)
• Canarypox vector platform for mammalian diseases is also a strong candidate
as an estimated platform
HVT-AI and other vector examples

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• Sub-unit antigens
• Well known ‘antigen factories’ like Baculovirus, yeast, Pichia pastoris…
• Find the gene of interest
• The relevant adjuvant
• Fast to build and develop
• ‘Simple’ on a regulatory standpoint (inactivated ‘by nature’)
• Questions: maternal antibodies, duration of immunity, broadness of
protection…
• Can be very useful with some diseases: best example: PCV2; was tested
with Flu
Other interesting technologies

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• Replicon vaccine
• Not inactivated, non-replicating virus
• Vaccine build with targeted gene of interest
• Able to enter target cells of vaccinated animals
• Gene of interest can be expressed by the cells: immune response
• But does not have the genetic material to multiply; no spreading to other
cells!
• Fast to build constructs
• Safe and a good candidate for registration as a technology/platform
(USDA already allowed this)
• Questions: duration of immunity, efficacy (but this is true for all construct
as it is a question of the good choice of targeted genes)
Other interesting technologies

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• Synthetic viruses and knowledge-based attenuation: clean and fully
characterized!
Other interesting technologies
Field sample

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Rift valley fever example
• Arbovirus, Bunyaviridae family;
mosquito vector and direct contamination
•Highly related to climate changes
• Ruminants (domestic, wild): economic losses due to death
and abortion
• Febrile disease in humans, fatal due to complications in <1% of cases
•Vaccines are not satisfactory
Culex spp Aedes sp

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A synthetic RVFV with a split M genome segment results in a
virus that is completely avirulent and highly effective vaccine
Rift valley fever example

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• Development consists of establishing and validating the manufacturing
process and then testing the vaccine for its shelf life, safety and efficacy
• These steps are followed by the registration and industrialisation processes
• Manufacturing process
• It should fulfil four main goals common to all veterinary vaccines: quality,
reproducibility, stability and an adequate cost of production
• Quality has two aspects:
• producing according to acceptable standards like GMP, USDA…;
• manufacturing according to a process allowing expressing the main
safety, efficacy, stability features singled our during the
research/feasibility phase
• This involves validated control tests that are the quality markers of the
production runs; with ‘New technology’ vaccines, composed of well
defined antigens and it is easier to monitor if the explored processes are
adequate or not to fulfil the set quality, safety and efficacy goals
• Finally pilot batches are produced
Vaccine development paradigm

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• Regulatory testing: vaccine pilot batches are tested according to a ‘regulatory’
analytical and clinical program covering:
• Validation of the planned manufacturing process
• Shelf life study
• Clinical trials to confirm the safety and efficacy claims
• Specific tests are required for genetically engineered non-inactivated
vaccines
• Timing and budget: for a new innovation (never registered before) from proof
of concept to the establishment of the ‘data package’ allowing the different
registration procedures:
• Poultry: 2 to 3 years and 2 to 4 M€
• Ruminants: 3 to 5 years and 4 to 10 M€
(depending on disease and claims)
• This could be reduced if the technology is already assessed on a
regulatory standpoint (see after)
Vaccine development paradigm

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• Registration dossier and procedures: all relevant data are gathered to
prepare dossiers for:
• Getting GMP permit in the country of origin (granted for each specific
vaccine)
• In the case of live genetically engineered vaccines a specific field
release procedure is usually needed
• If required by the target countries, to apply for a marketing authorisation
in the country of origin, even if this is not relevant for them (no disease
or market)
• Assessment by target country authorities of dossiers for new
technology vaccines:
• Specific training on these new technologies?
• Assessment by authorities of country of origin needed or not?
• How to deal with this procedure when urgent?
Vaccine registration paradigm

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• Registration dossier and procedures: timing
• Marketing authorisation timing (usual procedures):
-2,5 to 3 years, including specific procedure for field release, if the country
of origin is in Europe or the USA;
-then an additional 2 years to get the marketing authorisation in the target
countries. Can be much longer for ‘new technology’ vaccines.
• In any case, a long process…
Vaccine registration paradigm

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• What can be improved here to securely speed up the processes?
• Research phase is not the issue (with exceptions) as it now quick to
propose solutions
• Ideally the proposed solutions should be around already known
platforms: sub-unit antigens, live HVT vector, non-replicative replicon
systems… with predictable (not depending on a specific construct) and
clear safety benefits for the target species and the environment
• Assessment: when the proposed technology was already assessed by
registration authorities and Bio-Safety committees (from previously
registered vaccines): less tests might be asked for; focus can be on
efficacy with some confirmation safety and quality tests
• The US authorities (USDA) has already implemented this with some
platforms and technologies
Vaccine development & registration

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• What can be improved here to speed up the processes?
• When there is no disease in the country of origin, should authorities of
the target countries ask the applicant to register the vaccine at home?
• If not, how can they be sure that the proposed vaccine is safe?
• Use scientific assessment from recognised expert groups
• This is essential for target country authorities that had no chance to
be trained for ‘new technology’ vaccines
• Role of OIE, FAO, VICH to establish such recommend assessment
team, could be very important in this matter
• Once receiving a positive assessment, Authorities of the target
countries might give an exceptional license waiting for more data for the
final marketing authorisation (identical to systems in Europe and
elsewhere)
• Favouring establishment of regional vaccine players in the affected
zones? This is an important long-term goal; but wherever you are, you
need the same very experienced teams; also regulatory barriers are not
necessarily down between countries within a same region
(harmonisation is on the way though)
Vaccine development & registration

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Market access covers many aspects:
• Production: is there enough capacity to cover all the needs?
• Tight markets: with the increased recognition of vaccines as key and
comparatively cheap tools for healthy livestock and with the phasing out of
some alternative treatment solutions, we see already periods with tight
supply of vaccines in many parts of the world
• Manufacturing requires very skills teams that can only be built over many
years
• Extending capacity depends on two conditions:
• private initiative, willing to bet on new markets (including the ones
created by emerging diseases)
• Good policies helping these initiatives succeed
What about market access?

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• Registration procedures:
• A fair and predictable process ensuring that safe, efficacious vaccines
are registered
• Many challenges to implement this when there are urgent needs; some
solutions were already suggested
• Other market access challenges (basic but so important!):
• Supply chain: from the manufacturing site to the end customers
• In a few parts of the world (where these vaccines are in great needs)
this is challenging
• Transport and cold chain: refrigerated trucks and fridges
• More regional/local distributors close to the customers
• Veterinarians and vaccination/health technicians:
• More are needed on the field
• More trainings
• More schools
• Unfair competition
• With counterfeit products
• With ‘easier-access’ markets
What about market access?

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• Climate change along with other factors, triggers new and fast moving
disease patterns against which vaccines can make the difference
• New vaccine technologies using genetic engineering are now really mature
and already saving billions of animals every year; new ideas are ready to be
implemented; more effort is needed for some key unmet needs
• Development, registration, production of vaccines can be managed only by
very skilled teams/companies which are not so many in the world
• Vaccine registration procedure and timing might be challenging in many
occasions especially when new technologies are involved and needs are
urgent
• Accessing customers in some markets is sometimes very difficult and unfair
market competition can happen when vaccine supply is tight
• A better network of veterinarian, technicians and distributors, close to the
final customers are needed in many countries
Conclusions on the situation

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• All stakeholders must work on proactive and ambitious plans to ensure that
new vaccine solutions go from the laboratory to all customers, helping
companies/organisations which are willing to address these new markets
• Funding research
• Establishing solid technology platforms on which development and
regulatory experience can be built for future vaccines
• Set one reference assessment team for regions that do not have yet the
experience/expertise of ‘new technology’ vaccines
• Promote training and development of local and regional veterinary and
technical networks
• Establish new veterinary and health technician schools
In conclusion, in this context of climate change, science and
technology can do a lot, but much more is needed to get the vaccines
to the customers, where policy makers can make the whole difference!
Conclusions and proposed solutions

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My thanks to:
• Carel du Marchie Sarvaas, Executive Director, HealthforAnimals
• Jeroen Kortekaas, PhD, Central Veterinary Institute, Wageningen University
and Research Centre, the Netherlands
• Yannick Gardin, Director Science and Innovation, Ceva Animal Health
jean.de-foucauld@ceva.com
Thanks

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www.healthforanimals.org
HealthforAnimals
168 Avenue de Tervueren
1150 Brussels, Belgium
info@healthforanimals.org
www.healthforanimals.org
twitter! @health4animals
Ceva Santé Animale
10 Avenue de la Ballastière
33500 Libourne – France
Jean de Foucauld
jean.de-foucauld@ceva.com
www.ceva.com
Thank you