The use of vaccine for disease control : emphasis on local vaccine

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1 Vaccines & Biologicals for Disease Control in Malaysia : Public and Private Perspectives The use of vaccine for disease control : emphasis on local vaccine Abdul Rahman Omar aro@upm.edu.my

2 Outline of the presentation Conventional vs recombinant vaccines Common diseases of poultry and ruminants Vaccines against foodborne vs non foodborne diseases Vaccines against zoonotic vs non zoonotic viral agents Why viral diseases are difficult to control Issues in controlling bacterial diseases SWOT analysis in development of local vaccine Strategies to accelerate vaccine development and deployment

3 Increase cost of production Environment pollution Free World trade Outbreak of diseases Challenges of Animal Industry Consumer buying power and choice Market competition Traceability

4 Smallest virus, CAV (25 nm) and the largest virus, Fowlpox virus (250 nm) Poxvirus - FPV Circovirus CAV Adenovirus EDS76 Herpesvirus MDV, ILTV Coronavirus - IBV Reovirus Orthomyxovirus AIV Paramyxovirus NDV, SHS Retrovirus LL, REV

5 Disease control and prevention strategies Comprehensive control strategy : Management and biosecurity Diagnostics and surveillance Vaccination Education The ultimate goals are : to prevent introduction of disease to reduce losses from economic impact total elimination of the disease

6 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..

7 Vaccines and Vaccination Aim of vaccination : sterilizing immunity (prevent infection) disease immunity (prevent disease/mortality) blocking immunity (prevent virus shedding and transmission of disease) Active immunity versus Passive immunity (maternal antibody)

8 Infection & immunity infection Impact of Disease = Types of immunity Sterilizing Disease Blocking immunity Bolus of infection x virulence immunity

9 Outcome of infections depends on hostpathogen-environment interactions

10 Maternal Antibody and Vaccination Vaccination No maternal antibody Low titer maternal antibody High titer maternal antibody Neutralization of vaccine antigens by maternal ab. Half life of maternal antibody is 3 days. Maternal ab (1:512)(28 ) decrease 1:2 after 24 days (3 x n). Days

11 Live versus killed vaccines Live (attenuated/modified) Killed Possible of spread & mutation Stable and safe Single dose without adjuvant, neutralization by maternal antibody Multiple doses with adjuvant. Strong antibody response Induce mucosal, cellmediated immune responses and interferon production Strong antibody response Poor mucosal, cell-mediated immune responses and interferon production

12 Antigen Vehicle Vaccine System Adjuvant Delivery

13 Vaccine components 1. Antigens Whole inactivated or attenuated organisms Purified proteins & carbohydrates Recombinant proteins 2. Immune potentiators 3. Delivery systems Bacterial products Toxins and lipids Nucleic acids Peptidoglycans Carbohydrates & peptides Cytokines Small molecules Mineral salts Surface active agents Synthetic microparticles Oil-in-water emulsions Liposomes

14 Types of vaccines Conventional vaccine Recombinant vaccine Both types of vaccine can exist as live and/or killed depending on their use. Vaccine is about risk and benefit

15 Types of vaccines Conventional vaccines Killed (inactivated) vaccine Live-attenuated vaccine Recombinant vaccines Synthetic peptide Subunit Viral vector Bacterial vector/gene-deleted Reverse genetic DNA vaccine Virus-like particle

16 Vaccine combinations Different combinations : mono-, bi-, tri, & polyvalent (multivalent) Virus from the same family but different serotypes or from different family Cross-reactivity between different serotypes depending on the availability of common epitopes Synergistic and antagonistic effects depending on the entry and replication sites of the virus/bacteria

Adjuvants for inactivated vaccines Substances that enhance the immunogenicity of vaccines Current adjuvants primarily for inactivated vaccines.

17 Adjuvants for inactivated vaccines Substances that enhance the immunogenicity of vaccines Current adjuvants primarily for inactivated vaccines. Oil based (mineral oil) Aluminum salt (Alum) based [AlPO4, and Al(OH)3] Vaccine formulated in different emulsion types Work well, less tissue reaction

18 Do we need recombinant vaccine? Yes, if they provide clear advantages over the existing vaccines Vaccine is all about risk and benefit What are the limitation of current vaccines

19 Recombinant vaccines based on genetic engineering technology Synthetic peptide vaccine chemically synthesized sequences of protein (peptide) that encode for vaccine epitopes Subunit vaccine purified antigen from whole organisms or produced by prokaryotic/eukaryotic organisms via genetic engineering Viral vector vaccine fowlpox, herpesvirus, adenovirus.eg. FPVNDV, HVT-NDV (expressing foreign gene). Or gene-deleted vaccine of pseudorabies vaccine Reverse genetic vaccine paramyxovirus (NDV), orthomyxovirus (AIV), technically can be any RNA viruses. eg. NDV, AIV

20 Recombinant vaccines based on genetic engineering technology Bacterial vector vaccine express the vaccine antigen(s) (surface or internally). Or gene-deleted vaccine, eg. Spray E coli vaccine, live modified Salmonella vaccine DNA vaccines - instead of vaccine antigen, gene(s) that encode for vaccine antigen(s) in plasmids is used as a vaccine. Virus-like particle (VLP) - empty virus capsid expressing vaccine antigen(s). VLP can be produced in various systems including bacteria, mammalian, insect, yeast and plant cells.

21 Poultry viral vaccine technology Live attenuated and killed vaccines in different combinations : mono-, bi-, tri, & polyvalent. Killed vaccine uses oil or alum based adjuvants Ag-ab immune complex vaccine (IBDV vaccine) Vaccine delivery single versus mass vaccination Recombinant vaccines available commercially limited choice and only based on ; Viral vector vaccines - Fowlpox virus, Herpesvirus (HVT) and Adenovirus. Reverse genetics vaccines primarily for RNA viruses such as AIV and NDV.

22 Types of vaccines Conventional vaccines Killed (inactivated) vaccine Live-attenuated vaccine Recombinant vaccines Synthetic peptide Subunit Viral vector Bacterial vector/gene-deleted Reverse genetic DNA vaccine Virus-like particle Are these vaccines available commercially for poultry? Yes Yes No yet No yet Yes (HVT by several companies) Yes (E coli, Salmonella) Yes (NDV, AIV) No yet Soon

23 Challenge study Compare vaccine efficacy of vaccinated and control (nonvaccinated) groups Parameters that been measured ; Antibody (neutralizing) titer HI, VNT, ELISA Rarely require the measurement of T cells, cytokines or interferon productions Morbidity rate Mortality rate Immunosuppression eg. Bursal body, thymus weight Virus shedding, ocytes count, ciliostatis, etc Disease transmission to sentinel/susceptible animals

24 Vaccine assessment Efficacy study - the % reduction of disease in a vaccinated group of animal compared to an unvaccinated group Potency study to ensure that each consistently manufactured batch of vaccine provides a level of protection as determined in the original efficacy study throughout the products shelf life. Safety study to enhance our knowledge on the adverse events profiles of the vaccine

Factors that influence vaccine efficacy Factors associated with the vaccine itself Different serotypes/subtypes, level of cross-protection Live vaccine with varying virulence Vaccine antigen Factors

25 Factors that influence vaccine efficacy Factors associated with the vaccine itself Different serotypes/subtypes, level of cross-protection Live vaccine with varying virulence Vaccine antigen Factors associated with vaccine administration Handling of certain live vaccines QC of vaccine diluent Route of vaccination Dose of vaccination Factors associated with the animals/flock Level of maternal immunity Immunosuppression infection, mycotoxin, tolerance Stress The animals already infected with the disease Genetic of the animals Management conditions hygiene practise and biosecurity

26 Why viral diseases are difficult to control? Agent Threats to various species of avian, some agents are zoonotic Mutate constantly variant strains, more virulent, extended host range, vaccine/drug escape mutants Disease spectrum Cause a wide range of diseases mild to acute, persistence, concurrent infections, latent infection & immunosuppression Management Multi-age, intensive with high stocking density Control and preventive measures Difficult to diagnose especially subclinical and persistent infection Poor vaccine induced immunity Vaccination may complicate diagnosis

27 Common poultry viral diseases and vaccination Disease Avian Influenza Virus field strains versus vaccine strains HPAI H5N1, H5N8 and H5N6, LPAI H9N2, H7N9, other subtypes Subtype-specific vaccine based on killed vaccine, reverse genetic and viral vector of high homology ( 85%) to the field strain Implementation of vaccine may results in restriction in animal movements and trading. Surveillance by DIVA strategy Single serotypes, at least 18 genotypes (I to XVIII) Three pathotypes lentogenic, mesogenic, velogenic strains Live & killed vaccines, reverse genetic and viral vector vaccines Up to 3 vaccination with live and killed in broiler in endemic areas Vaccination prevent diseases but not prevent infection & virus shedding. Various factors contribute to ND being endemic in this region Newcastle disease Gumboro disease IBDV vaccine strains (mild, intermediate, intermediate plus, hot) Varying virulence and immunosuppression level Live, killed, viral vector and antigen- antibody complex vaccines 1 to 2 vaccination with more virulence strain depending on the presence of vv and maternal antibody profiles Various strains Mass, variant and Qx-like strains showing different tissue tropisms (respiratory, kidney) with poor cross protection Live and killed vaccine of different strains Vaccinations in combination with ND Infectious bronchitis

28 Common poultry viral diseases and vaccination Disease Fowl adenovirus Virus field strains versus vaccine strains Chicken infectious anemia Marek s disease Group III FAdV - EDS76 Group I FAdV different serotype 1 to 12, Killed vaccines from selected serotypes (4 and 8), some cross protection between virus of different serotypes in Group 1 Wide disease spectrum, can act as primary and secondary agents Vertically transmitted The virus infects hemocytoblast and precursor of T cells hence, cause anaemia & immunosuppression Vertically transmitted Birds infected with CAV show varying clinical signs based on challenge dose, age of the birds, level of maternal antibody and other concurrent infections Live attenuated vaccine strain in breeder before laying Live attenuated vaccines of serotype I, II and III Cell-free versus cell-associated vaccines Monovalent, bivalent and trivalent vaccine Vaccination at the hatchery with the vaccine strain(s) depending on the virulence of the field strain

29 Common poultry viral diseases and vaccination Disease Avian reovirus Virus field strains versus vaccine strains Virus classified into several genotypes based on sigma C gene Currently available vaccines are of limited effectiveness, likely due to the existence of many variants. Classical versus variant strains associated with poor cross protection Can cause wide spectrum of subclinical and clinical diseases associated with enteric, respiratory diseases, heart and liver Primary agent of severe arthritis syndrome Also associated with runting-stunting syndrome Is also one of the most common enteric viruses affecting commercial chickens which include adenovirus group I, chicken parvovirus, chicken astrovirus, avian nephritis virus, infectious bronchitis virus and avian rotavirus

30 Common ruminant viral diseases and vaccination Disease Foot and mouth disease Virus field strains versus vaccine strains Contagious ecthyma (ORF) FMDV 7 serotypes and numerous variants. Some serotypes have a restricted geographical distribution, e.g. Asia-1 while serotype O, occur in many different regions. No cross-protection between serotypes and sometimes protection conferred by vaccines even of the same serotype can be limited Four structural proteins- VP1, VP2, VP3 and VP4. VP1, VP2, VP3 are on the surface of the virus while VP4 is located internally DIVA is of considerable importance for the control of FMD especially in a previously FMD free country or in a country with sporadic outbreaks. Genus parapoxvirus, family poxvirus, a zoonotic virus. Increased in incidence due to high virulence virus and short term immunity Commercial live vaccine is available

31 How to control bacterial infection without antibiotics

32 Alternatives to antibiotics Vaccines Yeast Enzymes Probiotics Symbiotic = prebiotic + probiotic Alternatives to (Organic Acids) Antibiotics Acidifers (Organic Acids) Essential Oils Prebiotics phytogenic Antimicrobial Peptides Phytobiotics (Plant Extract) phytogenic

33 Issues in controlling bacterial diseases Resistance to antibiotics is high against selected bacteria in poultry. Some bacteria develop multidrug resistant bacteria, MRSA, VRE. Lack of new antimicrobials with new targets or mechanisms of action. Need to develop narrow-spectrum antimicrobials. No single non-antibiotic products (probiotics, phages, prebiotics, organic acids) that can fully replace antibiotics. Need more fundamental study on the mechanisms and also innovation to improve efficacy of non-antibiotic products. Need to develop more vaccines against foodborne bacterial infections

34 Vaccines against bacterial infections in poultry Foodborne pathogens E. coli strain O78 in poultry (APEC) Salmonella non-typhoidal (SE and ST) Campylobacter jejuni vaccines at R&D stages Non-foodborne pathogens Necrotizing Enteritis (Clost. perfringes producing B-toxin ) Infectious coryza (Avibact. paragallinarum serovar A, B and C) Fowl Cholera (Pasteurella multocida serotype 1 to 16) CRD (Mycoplasmosis MG and MS) Others Coccidiosis (Emeria species)

35 Common poultry bacterial disease and vaccination Disease Remarks Mycoplasmosis CRD is frequently triggered by respiratory viruses and subsequently complicated by bacterial invasion. Inactivated and live attenuated vaccines of different virulent, F strain (virulent) vs ts-11 and 6/85 strains (less virulent), Ideal live vaccine induce lifelong immunity, will not cause disease, transmissible via eggs and horizontal, distinguishes between vaccine and field strains Infectious coryza Inactivated vaccines, poor cross protection between serovar Vaccination timing depending on farm challenge Fowl cholera Highly contagious disease in a range of avian species including chickens, turkeys and water fowl (increasing order of susceptibility). Inactivated vaccines usually composed of serotypes 1, 3 & 4 Poor cross protection between serotypes Collibacilosis (APEC) Avian pathogenic E. coli (APEC) serotype O78. E coli infection can be primary or secondary after primary viral or Mycoplasma infections Killed injectable vaccine and gene-deleted spray live vaccine Mycoplasma gallisepticum Mycoplasma synovium Avibacterium paragallinarum serovar A, B and C Pasteurella multocida serotype 1 to 16

36 Common poultry bacterial diseases and vaccination Disease Remarks Salmonellosis typhoidal type Fowl typhoid (S. gallinarum) and pullorum disease (S. pullorum) Whole-cell killed Salmonella vaccines Of concern in chicken only. Control by maintaining farm free of Salmonella via strictly biosecurity, vaccination and management Salmonellosis non-typhoidal type (NTS) NTS serovars such as Typhimurium and Enteritidis are generalist pathogens with broad host specificity, a few S. enterica serovars such as Typhi, Sendai, and Paratyphi are adapted to the human. Vaccination is used primarily for public health reasons Both inactivated and modified live vaccines Vaccination may interfere with standard bacteriological and serological detection. If use live vaccine may spread the strain to environment. Policy of vaccination of breeders and laying hens differs considerably according to the country Salmonella enterica serovar Gallinarum biovar Gallinarum (S. gallinarum) Salmonella enterica serovar Gallinarum biovar Pullorum (S. pullorum) Salmonella enterica subspecies Enterica serovar Typhimurium (S. typhimurium) Salmonella enterica subspecies Enterica serovar Enteritidis (S. enteritidis)

37 Common ruminant bacterial disease and vaccination Disease Remarks Hemorrhagic septicemia P. multocida, primarily serotype B:2 Inactivated vaccine, poor cross protection with other serotype A Primarily in large ruminants Pneumonic Pasteurellosis P. multocida, primarily serotype A Inactivated vaccine injectable and spray vaccine Brucellosis B. abortus in large ruminants Live attenuated (S19) vs. live attenuated LPS-O deficient (RB51) vaccines B. melitensis in small ruminants Live attenuated B. melitensis REV1 vaccine Vaccination should be carried to control brucellosis in large and small ruminants Caseous Lymphadenitis (CLA) C. pseudotuberculosis, Gram +ve, facultative, intracellular coccobacillus. Vaccination with inactivated vaccine (Glanvac, Pfizer) Due to serovar/strains variation, efficacy of vaccine need to be tested against field strain

38 Common ruminant bacterial diseases and vaccination Disease Mastitis in large ruminants Remarks To reduce the use of antibiotic, vaccine should be developed. Polyvalent vaccine against several bacteria namely E. coli, Staph. aureus, Strep. agalaticae

39 Common ruminant parasitic disease and vaccination vaccinatio Disease Haemonchosis Remarks H. contortus is the most pathogenic gastrointestinal helminth of small ruminant Barbevax subunit (purified antigen) vaccine given SC to sheep and goat

40 Global veterinary vaccines

41 Process of Developing a New Drug & Vaccine years (human) 5 to 7 years (veterinary)

42 SWOT analysis in development of vaccine using local strains Strength Availability of local strain Expertise in development of inactivated vaccine for selected species of animals Weakness Local market too small, must go regional/international No GMP plant to produce the vaccine Difficult to find industry partner for commercialization Poor regulatory and biosecurity control with notifiable disease FMD, Brucella

43 SWOT analysis in development of vaccine using local strains Opportunities Threat Malaysia is still eligible for many grants Well structured and monitored animal (IACUC) study Cheaper to do research here compared to developed countries Strengthening of cooperation and teamwork between different agencies and industry in research and commercialization based projects High competitiveness, commercial vaccines from other countries Difficulties in co-financing of vaccine development project between academia, government and industry Lacks of funds..

44 Strategies to accelerate vaccine development and deployment To create centre/program for screening of new vaccine antigens and candidates against diseases of economic importance to the region To establish multi-stakeholder, small-scale manufacturing facilities capable of rapid production of pre-clinical grade vaccines for strengthening capacity on vaccine testing Improved cross-fertilization of knowledge between industry and academia To establish a flexible and innovative system of regulatory standards in setting up vaccines between experimental and commercial applications. Identification of best-practices and development of checklists for product development plans and implementation programmes

45 Conclusion Current conventional vaccines & delivery system are effective. Pathogens are moving targets zoonotic, variants, resistant mutants, more virulent strains and immunosuppressive. Vaccines require continuous improvement. Vaccine is all about risk and benefit ; - protection against infection, clinical disease and/or virus shedding and disease transmission. Recombinant vaccines are making it ways in animal industry. Recombinant vaccine should address the limitation of current conventional vaccines

46 Conclusion Vaccination is a complementary approach to biosecurity Most vaccines are almost 100% effective in control experiment where it able to induce robust immunity However, various factors influence vaccine efficacy in the field In the field, the major changes during vaccination are making the vaccine easier to apply, less expensive and more efficacious.

47 Thank You The Avian Infection and Immunity Research Group, UPM

48 For further details : wvpamy2018@gmail.com Website :

49 For further details : wvpamy2018@gmail.com Website :

50 Thank You AGRICULTURE INNOVATION LIFE 50

Poultry Disease Manual Characteristics And

Poultry Disease Manual Characteristics And Control Of Infections Written by: Dr. Jacquie Jacob, University of Kentucky Pullorum disease, also called Infection by Salmonella pullorum has also been reported