livestock vaccines: development and market access

Livestock vaccines: development and market accessFAO symposium: The Role of Agricultural Biotechnologies in Sustainable Food Systems and NutritionSession: Facing the challenges of climate change: Adaptation in the livestock and fishery sectors

Speaker: Jean de Foucauld, Senior Biology Expert, Ceva Santé Animalespeaking on behalf of HealthforAnimals

Rome, February 2016

2

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

3

www.healthforanimals.org

• 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

4

• 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

MalariaCholera

Influenza Diarrhoea Filiariasis Int. NematodesSleeping sickness Chagas West Nile Yellow FeverLyme disease

Meningococcal meningitisLeishmaniasis Dengue Japanese encephalitis St Louis encephalitis Rift Valley Fever Ross River Fever Murray Valley Fever

SchistosomiasisSTDs TrachomaTuberculosisRiver blindnessChildhood disease

High climate sensitivitySource: International Livestock Reseach Institute: Climate Change and Zoonoses Adaptation and Mitigation

5


• 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

6


• 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 ?

7


• 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

8


Goal of AI vaccines

1 – Infection

3 – Re-excretion

2 - Clinical expression

HIGHER RESISTANCETO INFECTION

REDUCTION OF RE-EXCRETION

CLINICAL PROTECTION

++

9


• 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

10

H5N1AIV

HA

HA gene

AIV genome

HVT

Non essentialgene

HVT = Vector

HVT

Insertion site

AIV = Donor

FC 126 strain

A/swan/Hungary/4999/2006(H5N1 clade 2 – subclade 2 AIV strain)

Inserted modifiedHA gene« insert »

11

Protection ≥ 80%Significantreduction of shedding

Cross cladeefficacy

ofVectormune® AI

HA insert

12

Protection ≥ 80%Significantreduction of shedding

Cross cladeefficacy

ofVectormune® AI

Vietnam 2004

Mongolia 2005

Egypt 2008

Indonesia 2007

Bangladesh 2011

Hungary 2006

Egypt 2010

Indonesia 2010

Egypt 2008

Egypt 2011

Germany 2014

13


• 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

14


• 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

15


• 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)


16


• Synthetic viruses and knowledge-based attenuation: clean and fully characterized!


Field sample

17

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

18

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

19


• 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

20


• 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

21


• 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

22


• 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

23


• 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

24


• 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

25


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?

26


• 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?

27


• 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

28


• 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

29


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

[email protected]

Thanks

30


HealthforAnimals168 Avenue de Tervueren1150 Brussels, [email protected]! @health4animals

Ceva Santé Animale10 Avenue de la Ballastière33500 Libourne – FranceJean de [email protected]

Thank you

mailto:[email protected]

https://twitter.com/Health4Animals



http://www.ceva.com/

livestock vaccines: development and market access

Education