Veterinary Vaccines: Day After Tomorrow

1
Veterinary Vaccines Day After Tomorrow

• Prof. (Dr) M. P. Yadav
• Former Vice Chancellor, SVBPUA T,Meerut

2
Edward Jenner (1749-1823)
3
Preamble

• Edward Jenner (1749-1823) Laid foundation for
  eradication of smallpox - the most dreaded pox
  disease in the human history
• Louis Pasteur (1885) Known for Animal Vaccines
  he immunized against anthrax by injecting a
  comparatively harmless attenuated culture of the
  Bacillus and later developed a vaccine for
  rabies.
• 1964 A killed rabies vaccine developed, required
  up to 30 painful shots in the abdomen. By 1980, a
  newer version requires only five shots in the arm
  to protect against this deadly disease.
• Continued product development has produced
  vaccines that are today safer, more effective
  easier to use than ever before.

4
Early Interventions Pre-Independence Phase

• 1899 Development of anti-rinderpest serum
• 1902 Anti-anthrax serum for cattle
• 1905 Haemorrhagic septicaemia serum
• 1906-08 Development of black quarter vaccine
• 1908-11 Treatment of surra in horses camels
• 1908 Development of polyvalent HS vaccine
• 1927 Development of GTV against RP
• 1940 Development of vaccine (R2B) against RD

5
Sustained RD Activities- Post-Independence Phase

• 1946-52 Updating FMD vaccines including
  crystal
• violet tongue
  epithelium
• 1951 Anthrax spore vaccine
• 1960-65 Control/eradication of AHS thru
  appropriate
• diagnostics, vaccine
  control strategies
• 1964-65 Goat kidney cell culture for RP
  calf kidney tissue
• culture rinderpest
  (TCRP) vaccine (helped in
• eradication of
  rinderpest)
• 1973 Irradiated sheep lung worm vaccine
• 1979 Theileria schizont vaccine for bovine
  theileriosis

6

• 1986-8 Inactivated goat pox vaccine
• 1999 Inactivated IBD vaccine
• 2000 CCPP vaccine for goats/sheep inactivated
  oil
• emulsified vaccine against
  IBH-HPS
• 2001 thermo resistant IBD vaccine
  thermo-resistant
• Vero cell-based TCRP vaccine
• 2001-2003 Development of live attenuated PPR
  vaccine
• 2003-2005 Live attenuated (LA) goatpox vaccine

7
Why Vaccines?

• Least expensive and cost-effective
• No broad-spectrum anti-viral agent.
• Resistance to Tamiflu by H3N2 and H1N1 Influenza
  viruses
• Help in prevention eradication of disease
  through herd immunity

continued..
8
Immune Responses to Vaccination
IMMUNITY
9
Vaccine Components

• Antigens
• Whole inactivated or attenuated organisms
• Purified proteins, glycoproteins and
  carbohydrates
• Recombinant proteins and glycoproteins

• 2. Immune potentiators
• Bacterial products
• Toxins and lipids
• Nucleic acids
• Peptidoglycans
• Carbohydrates, peptides
• Cytokines hormones
• Small molecules

• 3. Delivery systems
• Mineral salts
• Surface active agents
• Synthetic microparticles
• Oil-in-water emulsions
• Liposomes

Source Pashine, A. Valiante, N.M.  Ulmer, J.B.
(2005). Targeting the innate immune response with
improved vaccine adjuvants. Nature Medicine  11
S63 - S68.
10
New Vaccine Targets
11
An Ideal Vaccine

• Confers Solid Immunity
• Provides protection against a major challenge
  dose
• Early Protective immunity
• Provides protection against pathogen variants
• Lifelong immunity preferably in a single dose
• Prevents infection No disease carrier state
• Can be administered by mass immunization
• Safe
• None or minimal side effects

continued..
12

• Stable
• Storage over long periods - vaccine banks
• Thermostable - Elimination of cold chain
• DIVA
• Allows for clear identification of vaccinated
  animal and differentiation from infected animal
• Cost Effective
• Produced inexpensively and in large quantities

13
Types of Vaccines

• Inactivated vaccines
• Live attenuated vaccines
• Combination vaccines
• Live attenuated vaccine components PPRGP
  PPRSP
• Inactivated vaccine components FMDHS
• Subunit vaccines
• Expressed protein vaccines
• Synthetic peptide vaccines
• rDNA vaccines
• Vectored vaccines (Bacteria virus)
• Deletion Mutant vaccines
• Gene vaccines (mini, multi-gene vaccines)
• Edible vaccines
• Expression Library Immunization

14
Modified Live Vaccines

• MERITS
• Broad immunity
• One Dose Immunity
• Lasting Immunity
• Rapid onset of immune
• response

• DEMERITS
• Replication
• disease
• Reversion of
• virulence
• Extraneous
• agents
• Environment
• leak

15
Inactivated Vaccines

• DEMERITS
• Limited immunity
• Multiple Dose
• Short duration of
• immunity
• Slow onset of
• immune response

• MERITS
• Non-replicating
• Non reversion of
• virulence
• Can be used in at risk
• population

16
Drawbacks of Conventional Vaccines

• Reversion to virulence,
• Incomplete inactivation,
• Contaminations,
• Secondary effects
• inflammation, granuloma, fever, hypersensitivity,
  immuno-suppression
• Inability to differentiate vaccinated from
  infected animals
• Cold-chain requirement

17
Towards the Ideal vaccine

• Sub-unit Vaccines
• Recombinant Vaccines
• DNA Vaccines
• Edible Vaccines

18
Combination Vaccines

• Targeting more than one disease at one time for
  mass vaccination
• For human DPT MMR
• For Animals
• Candure DHL
• Duramune Max (canine adenovirus, canine
  parvovirus, canine leptospira, canine
  parainfluenza)
• FluVac Innovator (Eastern/western/Venezuelan
  equine encephalitisTetanus Equine
  rhinopneumonitis (EHV-1/4)Equine Influenza (type
  A1 and A2)

19
New Methods for Vaccine Development

• Live vaccines derived from naturally attenuated
  strains of same or similar virus
• ILT Virus in Poultry
• CDF-66 strain of RD virus isolated from
• Pigs
• HVT For Mareks Disease

20
New Methods for Vaccine Development

• Rotavirus
• 11 segments of double strand RNA
• Two encode
• VP4 (hemagglutinin)
• VP7 (glycoprotein)
• Co-infect tissue culture cells ? Reassortment
• 10 segments from monkey rotavirus
• 1 segment outer capsid protein of each of four
  major rotavirus strains
• Efficacy gt80

continued.
20
21
Bivalent Influenza Peptide Conjugate Vaccine
(BIPCV) An Universal influenza vaccine

• Novel vaccines, capable of inducing long-lasting,
  broad immunity against divergent strains,
  including potential pandemic viruses, are highly
  desirable
• Universal influenza vaccine, known as Bivalent
  Influenza Peptide Conjugate Vaccine (BIPCV),
  three injections over a six month period
• Low dose of the vaccine is well tolerated is
  safe
• This low dose vaccine evoked an immune response
  high antibody titers that is similar to levels
  associated with protecting small animals infected
  with influenza from serious disease and death.

21
22
Universal flu vaccine

• One protein on the surface of the influenza
  virus, the so-called M2 protein,
• remains unchanged in all human flu viruses known,
  including the strains that caused the pandemics
  in the last century.
• The new M2e vaccine on testing in mice
  provided total protection against 'A' strains of
  flu, without side effects.
• This universal influenza vaccine is the first
  example of a vaccine inducing a protective immune
  response that normally does not occur in nature,
  for example following infection by a virus or a
  bacterium.

22
23
Rinderpest Eradication

• 18th Century Lancisi suggested control methods
  that are still valid today.
• 1762 The world's first vet school opened in
  Lyons to teach Lancisi principle of RP
  control
• 1920s J. T. Edwards discovered that animals
  given attenuated RPV preparation were
  protected from RP for whole life.
• 1924 OIE created as an inter-governmental
  effort to combat RP
• 1927 GTV developed
• 1957 TCRP developed
• 1950 Inter-African Bureau of Epizootic Diseases
  was founded with a directorial plan to
  eliminate RP from Africa.
• 1987 PARC began operations in 34 African
  countries.
• 1992 NPRE launched for RP eradication by 1998
  via OIE pathway
• 1998 GREP, backed by FAO/OIE/IAEA, to eradicate
  RP by 2010.
• India now free of RP

24
FMD vaccine

• FMD endemic in India ( 15 of the world cattle
  popln)
• Annual revenue loss INR 2000 million due to FMD
• Loss of 3,508 million liters milk/yr (6.5 of
  the total annual national milk output)
• On average, annual losses per head of cattle
  baffalo in the country estimated at INR125.00
• Unless FMD IS ERADICATED, IT WOULD SPELL DOOM FOR
  THE RURAL ECONOMY IN India, as livestock
  contributed 6.71 billion per annum, accounting
  for 25 percent of the countrys agricultural
  output

25
PPR

• PPR outbreaks are reported regularly disease is
  endemic throughout India
• Mortality rate of 50 or more in susceptible
  sheep and goat populations
• Annual economic losses estimated to be INR 1,800
  million (US 39 million)
• Live modified vaccine commercially available

26
Sheep Pox

• Sheep pox endemic in India, Mortality 10-50
• Vaccination coverage only 2.22
• Economic losses decreased milk production,
  damage to the quality of hides and wool other
  production losses
• Potent Cell Culture vaccine available

27
Disease Control/Eradication by Mass Vaccination

• Many animal diseases controlled due to mass
  vaccination (HS,RD,FP,FMD,RP)
• Smallpox eradicated in 1980 (Human)
• AHS eradicated in 1965
• Rinderpest eradicated from India in 2003
• Polio controlled to greater extent (Human)
• FMD controlled to greater extent
• FMD-CP in 54 districts of 7 states
• National eradication program should be launched
  for PPR, Fowl Pox, Sheep Pox, Swine Fever

28
New Generation Vaccines at IVRI

• Gene vaccines
• Mono, bi-, tri-, multi-cistronic gene vaccines
• Minigene/multigene vaccines
• Expressed protein vaccines
• PPRV H protein expressed in Eukaryotic cell
  line
• RPV/PPRV H/F proteins expressed in silkworm

29
Combination Vaccines under development

• Thermo-resistant (tr) PPR vaccines for goats and
  sheep
• New live attenuated (LA) sheeppox vaccine
• tr-PPR (sheep isolate) vaccine LA sheeppox
  double combination vaccine
• tr-PPR (goat isolate) vaccine LA goatpox double
  combination vaccine
• tr-PPR (sheep isolate) vaccine LA sheeppox
  vaccine LA Orf triple combination vaccine
• tr-PPR (goat isolate) vaccine LA goatpox
  vaccine LA Orf triple combination vaccine
• ? All the above vaccines successful in lab
  trials
• ? Duration of immunity of Orf vaccine to be
  established

30
New generation Methods of Attenuation

• 1. Attenuation V/s Deletion Mutants
• Genetic engineering has now paved the way for
  attenuating pathogens by creating defined
  mutaions as well as deletion of a single or
  multiple genes
• Examples of mutant viral vaccines - pseudorabies,
  BHV-1, CSFV, FMD

continued.
31

• 2. Reverse Genetics

• Generation of viruses from cloned cDNA
• Avian flu vaccine (influenza A viruses)
  development by reverse genetics techniques
• Other vaccines by RG tech are
• human influenza virus (H5N1), avian influenza
  (Poulvac employing genes from H5N3, H5N1, H2N3,
  H1N1), swine influenza (H1N1), equine influenza,
  and Newcastle disease virus,

continued.
32
Adjuvants delivery system

• Potent adjuvants improve the effectiveness of
  vaccines by accelerating the generation of robust
  immune responses, sustaining responses for a
  longer duration, eliciting cytotoxic T
  lymphocytes
• Most of adjuvants enhance the humoral immune
  response, now emphasis on which increases TH1
  responses or CTLs
• Rational selection of vaccine adjuvants during
  vaccine design is hampered by limited knowledge
  of the immunophenotype evoked by most classical
  vaccine adjuvants

33
Market Scenario
Total 22.5 b
34
Current Scenario

• India fast growing vaccine market in the world
  (at about 900 million in 2006-07)
• Tough competition from the well established
  domestic companies.
• Developing nations require vaccines that are not
  included in the immunization schedules of
  developed countries.
• India is expected to fulfil the vaccine demand.
• India is a major buyer and producer of vaccines
• Developing Countries Vaccine Manufacturers
  Network (DCVMN) formed in November 2000.
• Out of 21 members, 16 are from Asian region

continued.
35
Indian Animal Vaccine Manufacturers

• Indian Immunological Ltd. a subsidiary of NDDB
• Venkateshwara Hatcheries, Indovax, Intervet India
  Pvt Ltd (now Schering Plough-Intervet), Brilliant
  Biologicals, Biomed Pvt Lts, Pasteur-Merial
• National control program on FMD (FMD-CP) -
  prompted many private sector undertakings like
  Intervet, Brilliant biologicals, Biovet Pvt Ltd
  to establish new plants for manufacturing of FMD
  vaccine in the country
• State animal husbandry Biologicals Units
• Andhra Pradesh, Assam, Bihar, Gujarat, Haryana,
• Jammu Kashmir, Karnataka, Kerala, Madhya
  Pradesh, Maharashtra, Orissa, Punjab, Rajasthan,
• Tamil Nadu, Uttar Pradesh, West Bengal

continued..
36
Challenges in Veterinary Vaccine Sector

• 1. Cost Effectiveness Economy of vaccine
  production
• 2. diseases where vaccine is most demanding -
  Classical swine fever, sheep and goatpox,
  bluetongue, FMD, EHV-1/4, strangles,
  haemorrhagic septicaemia (HS), etc
• 3. Vaccine updation
• Many RNA viruses (FMD virus, bluetongue virus,
  and influenza viruses) are highly variable and
  require updation of vaccine very frequently
• 4. Potency Testing
• batch potency tests - involve administration of
  vaccine to target species or laboratory animals
• Alternate method (s) need to be established

continued.
37

• 5. Use of deletion mutants for vaccine
  preparation
• 6. Bio safety and bio security concerns
• GMP, GLP to be fulfilled
• 7. Immunomodulation
• Use of adjuvants and Cytokines (Immunosuppression,
  Killed Vaccines)
• 8. Developing vaccines for longer duration of
  immunity
• 9. Safety of Vaccine for Foetus and New Born
• 10. Vaccine Response vis-à-vis nutritional status
  of the animal
• Vitamin A deficiency may compromise immunity
• Protein and Energy deficiencies may adversely
  affect Immune Response

continued.
38

• 11. Vaccination vis-à-vis genetic status of the
  animals
• -Variation in MHC antigens
• 12. In-ovo- Immunization in Poultry
• 13. Immunization of young animals
• 14. Easy Vaccine Administration
• (oral, In drinking Water, Aerosol)

continued.
39

• 15. Vaccine regulatory issues
• veterinary vaccine needs to meet the regulatory
  norms that pave the route to marketplace
• Traceability of the vaccinated animals
• Immunization card
• 16. Filling the gap between demand and supply
• Developing countries are still far behind in
  terms of number of vaccines, their quality and
  quantity.
• 17. Thermostable Vaccines
• 18. Optimum Antigenic mass in the Vaccine
• 19. Multivalent Vaccines

continued.
40
The Way Forward..

• India must evolve its own national strategies to
  meet its vaccination needs within its budgetary
  constraints.
• The first and foremost element in this strategy
  must be the decisive intervention of the Indian
  government to meet the shortfall in the
  veterinary vaccines.
• The suitability of imported vaccines to deal with
  Indian pathogenic strains also needs to be
  conclusively established wherever necessary.
• Effective Disease surveillance system.
• With a strong will and a small amount of
  planning, the current situation in India can be
  reversed, and India can even play a major role in
  meeting the Asian shortfall in veterinary
  vaccines.

41
Vaccines
? ? Successes of the Past Possibilities for the
Future
42
Thanks