recent advances in vaccine and it's development and phases of clinical trials and FDA approved vaccines and vaccines in pipeline

1. Recent advances in
Vaccine Development
Dr. Mansij Biswas
Dr. Pooja Vaidya
Dr. Anup Petare
Department of Pharmacology & Therapeutics
Seth GS Medical College & KEM Hospital

2. “A vaccine is a biological preparation that improves immunity
to a particular disease. A vaccine typically contains an agent
that resembles a disease-causing microorganism, and is often
made from weakened or killed forms of the microbe, its toxins
or one of its surface proteins. The agent stimulates the body's
immune system to recognize the agent as foreign, destroy it,
and remember it, so that the immune system can more easily
recognize and destroy any of these microorganisms that it later
encounters”– WHO 2015

4. Milestones in vaccine development
1798: Edward Jenner invented
smallpox vaccine
1885: Louis Pasteur developed the first
vaccine to protect humans against rabies
1927: BCG vaccine recognized
1955: Dr. Jonas Salk’s inactivated polio vaccine licensed,
beginning the decline of polio worldwide.

5. 1963 : Dr. Albert Sabin introduced trivalent oral polio vaccine
The first measles vaccine licensed
1971 : The MMR vaccine licensed.
1982 : Hepatitis B vaccine becomes available.
Blumberg & Millman Irwing
1995 : Varicella vaccine is licensed.
Hepatitis A vaccine licensed.
Acellular pertussis vaccine licensed
Milestones in vaccine development

6. 2003: The first live attenuated influenza vaccine(FLUMIST) licensed
for use in people from 5 to 49 years of age.
2005: FDA licenses the meningococcal conjugate vaccine to
prevent invasive meningococcal diseases (MENATRA)
2006: FDA licenses the HPV (GARDASIL) and Rotavirus vaccines
(Rota Teq)
2008: Two dose rotavirus vaccine (ROTARIX) approved
2009: Influenza A (H1N1) vaccine approved
Milestones in vaccine development

7.  They help healthy people stay healthy
 Benefit not only individuals but also communities, and even entire
populations (Herd immunity)
 For most vaccines, their impact on communities and population is
more rapid than that of many other health interventions, cost
saving as well
 Reduce prevalence and incidence of diseases, sometimes
eradicates the disease itself (small pox, polio)
CDC has put vaccination at the top of its list of ten great public
health achievements of the 20th century.
“With the exception of safe water, no other modality, not even
antibiotics, has had such a major effect on mortality
reduction”….WHO
What is so special about vaccines?

8. Concept of vaccination:

9. Types of vaccines
 Whole-Organism Vaccines
 Killed (Pertussis, Cholera, Rabies, Influenza)
 Live Attenuated (BCG, OPV, Measles, Mumps, Rubella)
 Purified Macromolecules as Vaccines
 Toxoids (Diphtheria, Tetanus)
 Cellular fractions:
• Capsular polysaccharides (pneumococcal)
• Cell wall polysaccharides (meningococcal)
• Surface antigens (Hepatitis B polypeptide)
 Combinations (DPT, MMR)

10.  Newer approaches:
 Recombinant vaccine
 DNA vaccine
 Multivalent Subunit Vaccines
 According to microorganism
I. Bacterial (BCG, Cholera, Typhoid, toxoids)
II. Viral (OPV, MMR, Rabies, Hepatitis)
III. Rickettsial (Epidemic typhus)
 According to indication
I. Preventive
II. Therapeutic
10

11. Basic steps of
vaccine production

12. SELECTING THE STRAINS FOR
VACCINE PRODUCTION
GROWING THE MICRO-
ORGANISMS- PROPAGATION
ISOLATION & PURIFICATION
INACTIVATION OR ATTENUATION
FORMULATION OF VACCINE
QUALITY CONTROL AND LOT RELEASE
Upstream
processing
Downstreamprocessing

15. Future prospects
•Use of recombinant DNA technique to insert the gene coding for
the protein of interest into the genome of avirulent virus that can
be administered as vaccine
•Including in the vaccine only those subviral components needed
to stimulate protective antibody, minimizing occurrence of adverse
reactions
•Use of purified proteins isolated from purified virus or synthesized
from cloned genes (recombinant Hep B vaccine containing viral
proteins synthesized in yeast cells)- forming empty VLP
•Use of synthetic peptides corresponding to antigenic
determinants on a viral protein, thus avoiding reversion to
virulence since no viral nucleic acid is present (newer HIV
vaccines)

16. •Development of edible vaccines where transgenic plants
synthesizing antigens from pathogenic viruses provide new
cost effective way of vaccine delivery
•Use of naked DNA vaccines in which recombinant plasmids
carrying the gene for the protein of interest are injected into
hosts and the DNA produces immunizing protein
•Administration of vaccines locally to stimulate antibody at the
portal of entry (aerosol vaccines for respiratory disease
viruses)
•Needle free adminstration: oral (Live Bacterial Vector,
Particulate Formulations, Mucosal Adjuvants)
transcutaneous, liquid jet injection and epidermal powder
immunization, microneedle-based injection system

17. Reverse Vaccinology
• Conventional approach : Pathogenic organism is grown in the
laboratory and from which a limited number of antigens are isolated.
• Genes most likely to correspond to conserved antigens are picked
out that could be used in a vaccine.
• Genes inserted into a different, rapidly multiplying organism – such
as yeast
•Classical reverse vaccinology: group B meningococcal vaccine.

18. Conjugation technology
• The sugar molecules linked on the outer envelopes of certain bacteria
such as the pneumococcus, the meningococcus, and the Hib bacterium –
are Conjugated to strongly immunogenic “carrier” proteins.
Old New
Protective immunity in children under two
years of age.
No Yes
Create a long-lasting memory of the
pathogen
No Yes
Herd immunity (e.g. Pneumococcus) NO Yes

19. DNA Vaccines: a promising future
•DNA vaccines are third
generation vaccines, and are
made up of a small, circular
piece of bacterial DNA
(called a plasmid) that has
been genetically engineered
to produce one or two
specific proteins (antigens)
from a micro-organism. The
vaccine DNA is injected into
the cells of the body, where
the "inner machinery" of the
host cells "reads" the DNA
and converts it into
pathogenic proteins

20. Advantages of DNA Vaccines
•Cheaper and easier to produce
•Large rapid GMP manufacturing capabilities
•No need to handle infectious pathogens during production
•Safer
•Can elicit both humoral & cell mediated immunity
•Stable at a broad range of temperature (no cold-chain requirement)
•Can be designed and produced by genetic engineering to have
only the desired antigens or antigenic sequences (epitopes) in the
vaccine
•Ability to immunize against multiple antigens and/or Pathogens
•Nonviral and no induction of anti-vector immunity

22. Vaccine Development
Process
development
Clinical
development
Assay
development
 Bulk
manufacturing
 Product finishing
 Phase I
 Phase II
 Phase III
 Purity
 Potency
 Stability
Discovery

23. Nature, 463–469 (26 May 2011); A 2020 vision for vaccines against HIV, tuberculosis and malaria

24. 1902: Biologics Control Act/ Virus-Toxin Law
1997: FDA Modernization Act
Clinical development
Pre-IND
Identification of
product,
component, antigen
Manufacturing
process
Preclinical studies
Investigational
new drug
IND application
Clinical studies
(Phase I, II and III)
Non clinical
development studies
Licensing
Biologics license
application
Preapproval lot
release inspection
Bioresearch
monitoring
Review of label
Post approval
Lot release testing
Biannual or annual
facility inspections
Post marketing
surveillance

25. Pre-IND stage
 Identification of components and antigens
 Preclinical testing
 to rule out overt toxicity
 identify potential toxic effects that might occur during the
clinical trial and reversibility of the toxicity
 Requirements for preclinical toxicity studies depend on,
 vaccine’s potential risk/benefit consideration
 target population
 available clinical data from the use of related products
 availability of animal models

26. Investigational New Drug Stage
Phase I
Safety &
immunogenici
ty study
Phase II
Safety/ Dose
ranging study
Phase III
Large scale
safety/efficacy
study
 in small numbers (e.g. 20-100) of healthy adults, apprx 1 year
 to evaluate vaccine safety and immunogenicity
 includes study of dose and route of administration
 Information about the induction of cell-mediated immunity, the
cross reactive antibodies and/or interaction pre-existing antibodies
which might affect immune system is also obtained.

27. Investigational New Drug Stage
Phase II
 Initial trials examining safety, effectiveness (immunogenicity) dose
range & pharmacokinetics
 In several hundred volunteers forming the target groups, like,
children, adults or those at risk of exposure to pathogens
 1-3 years
 To obtain preliminary estimates on rates of common adverse events

28. Investigational New Drug Stage
Phase III
 provides the critical documentation of the vaccine’s safety and
effectiveness needed to,
 evaluate the risk/benefit relationship
 to support licensure
 typically enrol several thousand subjects.
 3-5 years
• Manufacturing reproducibility is typically addressed by
evaluation of lot consistency and ensuring process validation

29. Vaccine licensure
 based on demonstration of safety, immunogenicity, and efficacy
 based on ability to manufacture product in a consistent manner
Biologics license application (BLA)
 Data derived from nonclinical and clinical studies
 Description of manufacturing methods
 Compliance with GMP requirements
 Documentation of all raw materials used
 Data establishing stability of the product
 Samples representative of the product
 Description of equipment and facility of each location involved in
the manufacture

30. Lot-Release Testing includes,
 Sterility, purity: detects the presence of bacterial or fungal
contaminants
 General safety: detects toxicity
 Identity: verifies that a product induces specific antibodies after
vaccination
 Potency: verifies immunogenicity, antigen content, or chemical
composition
 Tests for removal of process contaminants
 Pyrogenicity: detects the presence of fever inducing substances
 Also, constituent materials such as diluents and preservatives
must meet standards for sterility
Post approval stage

31. Extended stability studies
• Tropical countries like India
• Maintenance of cold chain
Lot to lot consistency studies
Periodic facility inspections
Licensed establishments are inspected at least every 2 years except
for those facilities that manufacture influenza vaccines; these
establishments are inspected annually

32. Post approval stage
Post marketing Surveillance
 Necessary component of vaccine-safety monitoring
 Done in large populations over longer periods of time
 Important objectives:
 to monitor increase in known reactions
 to identify rare adverse reactions not detected during pre-
licensure studies

33. 1986: National Childhood Vaccine Injury Act
health professionals and vaccine manufacturers to report specific adverse
events after the administration of particular vaccines
1990: Vaccine Adverse Event Reporting System (VAERS)
established under the joint administration of CDC and FDA to collect
reports of suspected adverse events after administration of all US-
licensed vaccines
FDA and CDC use VAERS data to monitor vaccine safety
Adverse event reporting

34. Bridging studies in vaccine trials
• Done when there is change in vaccine composition with regard to
adjuvant, preservative, or a change in manufacturing process, site
or scale
• Immunogenicity data can easily be used to extrapolate efficacy
results when the immune response correlates with vaccine
induced immunity
• Designed to demonstrate equivalent immunogenicity i.e. exclude
a clinically significant difference in the immune response between
the population in whom efficacy was shown and the population to
whom those efficacy results are extrapolated
Fritzell B; ‘Bridging studies’; Dev Biol Stand. 1998;95:181-8.

35. Special concerns
 A small risk of infection with active or
live - attenuated micro-organisms
 Participants in control groups or when subjected to ineffective
vaccines run a risk of contracting the disease
 Risks associated with vaccines produced by recombinant DNA
techniques are not completely known
 Post trial access to the vaccine should be available to the control
group. But, children in control arm may cross the age when vaccine
is protective.
 When a trial of HIV preventive vaccine is being conducted, positive
serology may result after the vaccination.

37. Limitations of Current Vaccines
• Single disease prevention
• Require Multiple doses
• Not 100 % effective
• No sustained Protection
• Though less, but have adverse reactions
• Most are not safe in pregnancy and immunodeficiency
• Biological & environmental stability- difficult
• Cost effectiveness
• Risk of infection with live-attenuated micro-organisms

41. Need for development of newer vaccines !!
 No effective vaccine available for major mortality causing diseases
like Malaria, TB and AIDS
 Need for effective, potent & stable vaccines
 Minimal/No adverse reactions
 New Delivery Techniques for better compliance
 Lower cost
 Protect against more diseases & sustained protection
 Emerging and Re-emerging Diseases
 Era of progressing antibiotic resistance
 Certain Pandemic Non-Infectious Diseases

42. Recent advances

43. Menveo (meningitis vaccine)
 Quadrivalent conjugate vaccine containing
the Neisseria meningitidis serogroups A, C, Y and W-135
 For active immunization to prevent invasive meningococcal
disease in persons 11 to 55 years of age
 Single 0.5 ml I.M. injection
 FDA approval was based on demonstration of efficacy in
randomized, multicentre, active controlled clinical trial
conducted in the 3539 subjects
 Adverse events: pain at the injection site, headache, myalgia

44. Prevnar 13 (Pneumococcal 13
valent Conjugate Vaccine)
 Conjugate vaccine containing capsular antigens
of Streptococcus pneumoniae serotypes,
1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F
 Indicated for active immunization for the prevention of invasive
disease caused by Streptococcus pneumoniae for use in children 6
weeks - 5 years
 Approval was based on demonstration of non-inferiority compared
to U.S. licensed 7-valent pneumococcal conjugate vaccine (PCV 7) in
2 month-old infants
 Adverse events : injection site reactions, fever, decreased appetite,
irritability, sleep issues, diarrhoea, vomiting, rash

45.  Vaccine schedule:
o For Infants and Toddlers: Four-dose series 0.5ml I.M. at 2, 4, 6,
and 12-15 months of age
o For Unvaccinated Children:
 7-11 months of age: 3 doses at 0.5 mL - the first 2 doses at least
4 weeks apart; third dose after the one-year birthday,
separated from the second dose by at least 2 months.
 12-23 months of age: 2 doses at least 2 months apart at 0.5mL.
 24 months - 5 years: 1 dose at 0.5mL.
Prevnar 13 (Pneumococcal 13
valent Conjugate Vaccine)

46. Menactra (Meningococcal Polysaccharide
Diphtheria Toxoid Conjugate Vaccine)
 Invasive meningococcal disease by Neisseria meningitidis
serogroups A, C, Y and W-135
11-55 years 2-10 years 9 months
2004 2007 2011
 Safety evaluated in 4 clinical studies in 3700 participants
 Adverse events: injection-site tenderness and irritability
 9 - 23 months: Two doses 0.5 ml each I.M. 3 months apart.
 2 - 55 years of age: 0.5 ml single dose I.M.

47. Other official recommendations
 Zostavax, live attenuated vaccine
 Approved for use in 50 to 59 years of age
 Based on a multicenter study in 22,000 people, 50-59
yrs, which showed that Zostavax reduced the risk of
developing shingles by 70 percent
 In January 2011, Menveo approved for use in children 2 - 10
years
Based on 2 RCT’s (V59P20 & V59P8), Menveo better than
innovator polysaccharide vaccine
 In August 2013, USFDA approved Menveo for use in infants as
young as 2 months of age
Based on demonstration of immunogenicity in V59P23 trial

48. MenHibrix (Conjugate vaccine)
 For active immunization against invasive disease caused by
Neisseria meningitidis serogroups C and Y and Haemophilus
influenzae type b in children 6 weeks - 18 months of age
 Four doses 0.5 ml each I.M. at 2, 4, 6 and 12 months of age.
 First dose may be given as early as 6 weeks of age and fourth
dose as late as 18 months of age
 Safety demonstrated in 6767 subjects and Immunogenicity
demonstrated in 2925 subjects
 ADR: Injection site pain, irritability, fever and loss of appetite

49. Flucelvax (Influenza vaccine)
 Inactivated trivalent cell-culture-derived vaccine
against A (H1N1, H3N2) & B subtypes
 For active immunization in adults aged 18 years and older
 Single 0.5 ml I.M. injection
 The FDA approval of Flucelvax was based on,
 RCT during the 2007-2008 influenza season in 11400 adults
aged 18 - 49 years showed an 83.8% efficacy rate
 Immunogenicity confirmed in 3 clinical studies in 1353
subjects
 Adverse events reported: injection site reaction, headache, fatigue

50. Fluarix Quadrivalent influenza vaccine
 First intramuscular Quadrivalent influenza vaccine
 3 years of age and older
 Recommended dose:
 3 – 8 years: Two doses 0.5 ml each I.M., at least 4 weeks
apart
 9 years and older: Single 0.5 ml I.M.
 Adverse events: injection site pain, headache, fatigue, myalgia
FluLaval is another Quadrivalent influenza vaccine approved for
use in persons > 3 yrs of age

51. Flublok (seasonal influenza vaccine)
 Trivalent recombinant vaccine
 For active immunization against influenza subtypes A (H1N1 &
H3N2) and type B in adults 18 - 49 years of age.
 Single 0.5-mL intramuscular injection
 An RCT in 4,648 healthy adult subjects demonstrated
immunogenicity
 Adverse events noted were injection-site reaction, headache, fatigue,
myalgia
Received accelerated approval in Oct 2014 for use in persons 50
years of age and older

52. Fluzone Quadrivalent influenza vaccine
 Inactivated Quadrivalent vaccine
 6 months of age and older
 Dose:
 6 months to 35 months: 2 doses of 0.25 ml each I.M 4 weeks apart
 36 months to 8 years: 2 doses of 0.5 ml each I.M 4 weeks apart
 9 years and older: Single I.M 0.5 ml injection
 Approval based on immunogenicity studies in 1419 children, 6 – 35
months of age and in 2101 children, 3 to 8 years of age
 Adverse reactions: Injection site reactions, irritability, abnormal
crying, myalgia, fever and vomiting

53. TRUMENBA (Meningococcal Group B
Vaccine)
• Approved on October 29, 2014 via accelerated approval
• First vaccine licensed in the US to prevent invasive
meningococcal disease by Neisseria meningitides serogroup
B in individuals 10 - 25 years of age.
• Approval was based on demonstration of immune response in
3 randomised trials in 2800 adolescents
• Three doses of 0.5 mL each by intramuscular injection at 0, 2
and 6 months
• ADR: Pain at injection site, headache, myalgia and fatigue

54. Gardasil 9 (Human Papillomavirus 9-valent
recombinant Vaccine)
 Cervical, vulvar, vaginal and anal cancers caused by HPV types
16, 18, 31, 33, 45, 52 and 58
 Genital warts caused by HPV types 6 or 11
 Girls and women 9 - 26 years of age
 0.5-mL intramuscular injection at 0, 2 months, 6 months
 Added protection against five additional HPV types
31, 33, 45, 52 and 58
 RCT in 14,000 females, 16 - 26 yrs showed,
 97% effectiveness in preventing cervical, vulvar, vaginal
cancers & 78% in preventing anal cancer
• Adverse reactions: injection site reactions and headache

55. Afluria needle free
influenza vaccine
 Trivalent inactivated influenza vaccine
 5 years of age and older
 Safety & efficacy demonstrated in a RCT conducted in 15,044
subjects
 Immunogenicity established in an RCT in 832 subjects, 5 to 17
yrs
 Dose:
 5 – 8 yrs: 1 or 2 doses of 0.5 ml each I.M, at least 4 weeks
apart
 9 yrs and older: Single 0.5 ml dose via needle-free delivery
system approved by the FDA
 ADR: Pain at injection site, headache, myalgia and fatigue

56. Fluzone Intradermal Quadrivalent
 Inactivated Quadrivalent vaccine against
subtype A (H1N1 & H3N2) & B virus
 Approved for use in persons 18 - 64 years of
age
 Single 0.1 mL dose for intradermal injection
 Approval based on Immunogenicity studies
in 2249 participants
 Adverse reactions: injection-site reactions,
headache and myalgia

57. Vaccines in pipeline
 Preventive
 Therapeutic

58. HIV vaccine
 Urgent global priority
 An ideal HIV vaccine goal: Sterilizing immunity
 Realistic goal: to prevent viremia

59. HIV vaccine
Candidate
Vaccine
Component
First
generation
Based on envelope proteins especially gp120
Second-
generation
Live vectors (such as canarypox) or naked DNA
coding for different HIV genes
Third-
generation
Regulatory nonstructural proteins eg. Tat (a
transactivator of HIV gene expression) and Nef (a
multifunctional protein)
Majority of these vaccines are in phase I and phase II studies

60. HIV vaccine

61. HIV vaccine efficacy trial RV144
 Tested the “prime-boost” combination of two vaccines:
 ALVAC HIV vaccine (Prime)
 AIDSVAX vaccine (Boost)
 Lowered rate of HIV infection by 31.2 % with maximum
protection at 6 – 12 months
 ALVAC is a recombinant canary pox vector vaccine that
express antigens of HIV-1 subtypes B (gp41 )and E (gp 120)
 AIDSVAX is a bivalent HIV envelope glycoprotein 120 vaccine
 IgG3 antibodies binding to the V1/V2 region of HIV’s envelope
protein correlated with lower infection rates among those
who were vaccinated.

62. HIV vaccine RV 305 trial
• Ongoing Phase IIB trial
• To assess safety and tolerability of late boost regimens of
AIDSVAX alone, ALVAC alone, or ALVAC/AIDSVAX combination
in HIV-uninfected participants from RV 144
• Goal of the secondary boost is to try to extend and increase the
immune response seen in RV144
 Ongoing Phase I trial
 To gather more immunogenicity data in 360 new volunteers
using R144 regime
HIV vaccine RV 306 trial

63. tgAAC09
 A recombinant adeno-associated virus type 2, HIV-1 subtype C
vaccine
 Does not contain HIV virus
 Phase I trial in 80 HIV-uninfected healthy volunteers showed
that vaccine was safe, well-tolerated, and modestly
immunogenic
 Phase II, Placebo-controlled, Double-blind, Dose-escalation
Trial to Evaluate Safety and Immunogenicity is completed in
2012
 Trials to evaluate higher doses and boost injections is ongoing
in Africa.

64. “Our goal is not to completely
eradicate the infection - that would
be very difficult - but to produce a
vaccine that will prevent not
infection but disease. I think this is
more possible”
Luc Montagnier

66. Ebola virus disease (EVD)
cAd3
 Vectored vaccines: Ebola virus glycoprotein is presented in a
replication-incompetent chimpanzee adenovirus 3
 Phase 1, dose-escalation trial in 20 healthy adults with bivalent
form and in 60 healthy adults with the monovalent form is
ongoing
rVSV
 Vectored vaccines in which the Ebola virus glycoprotein is
presented in a replication-competent vesicular stomatitis virus
 First phase 1 trial of the rVSV vaccine is slated to begin soon
Hong JE, Hong KJ, Choi WY, Lee WJ, Choi YH, Jeong CH, Cho KI. Ebola hemorrhagic Fever and the current state of vaccine development.
Osong Public Health Res Perspect. 2014 Dec;5(6):378-82

67. Malaria
Pre-erythrocytic vaccines:
prevent clinical manifestation
Erythrocytic vaccines:
prevent invasion of RBC by merozoites & speed parasitized
RBC clearance
Decrease the symptom severity
Transmission blocking vaccines:
blocks human to human transmission

68. Malaria
Circumsporozoite
protein (CSP)
Merozoite surface
protein (MSP)
Apical membrane
antigen 1 (AMA-1)
Multiple Antigen Peptide (MAP) Vaccines
 Effective immunity
 Currently in preclinical stages
Babita Mahajan et al. Multiple Antigen Peptide Vaccines against Plasmodium falciparum Malaria infection and Immunity
2010:70(11):4613‐4624

69. Malaria
RTS,S/AS02A
• Pre-erythrocytic subunit vaccine
• Fusion of surface CSP antigen with the HBsAg, formulated with
the AS02 adjuvant system
• Acceptable side-effect profile and immunogenicity confirmed in
children 6 weeks of age or older
• Phase 3 trial in 15,460 children in two age categories:
6 to 12 weeks of age and 5 to 17 months of age, showed
protection against clinical and severe malaria up to 18 months
after vaccination.
Sacarlal J et al. Long-term safety and efficacy of the RTS,S/AS02A malaria vaccine in Mozambican children. J Infect Dis. 2009 Aug
1;200(3):329-36

70. Dengue
CYD-TDV
 Live attenuated tetravalent vaccine
 Vaccine efficacy of 57%: Phase III study in 10,275 children aged
2 to 14 years in 5 countries in the Asia-Pacific revealed
 3 doses given 6 months apart (at 0, 6 and 12 months)
 First study of the vaccine on Indian adults aged 18-45 years at
five sites found: vaccine safe & immunogenic
 A second Phase III trial: ongoing in 31000 subjects of Latin
America
Da Costa VG, Marques-Silva AC, Floriano VG, Moreli ML. Safety, immunogenicity and efficacy of a recombinant tetravalent dengue vaccine:
a meta-analysis of randomized trials. Vaccine. 2014 Sep 3;32(39):4885-92

72. Tuberculosis
Nonliving vaccines: purified antigen
subunit vaccines and DNA vaccines
Live mycobacterial vaccines: attenuated strains or BCG
strains
Use of viral vectors such as adenovirus or vaccinia virus

73. Tuberculosis
Boosting BCG with MVA85A
 Modified Vaccinia Ankara virus expressing antigen 85A
 Induces higher levels of both antigen specific CD4+ T and
CD8+ T cells when used together with BCG
 Phase I clinical trials showed excellent safety profile
 A randomised, placebo-controlled phase 2b trial in 2797
infants revealed 17. 3% vaccine efficacy against
tuberculosis
McShane H, Pathan AA, Sander CR, Goonetilleke NP, Fletcher HA, Hill AV.Boosting BCG with MVA85A: the first candidate subunit vaccine for tub
in clinical trials. Tuberculosis (Edinb). 2005 Jan-Mar;85(1-2):47-52
.

74. Tuberculosis
Boosting BCG with Mtb72F/AS02A
 Fusion protein derived from Mtb39A & Mtb32A antigens with
AS02A adjuvant system
 Under development for:
 Prevention of primary TB infection in young children of
highly endemic areas
 As an adjunct to treatment for TB in adolescents & adults.
 Phase I study in PPD-negative TB-naïve, healthy adults revealed
safety and immunogenicity in healthy adults when given in as
0, 1, and 2-month schedule
 Currently Phase II trial: Healthy PPD-positive volunteers aged 18-
50 years is ongoing
Leroux-Roels et al, Evaluation of the Safety and Immunogenicity of Two Antigen Concentrations of the Mtb72F/AS02A Candidate Tuberculosis Vaccine
in Purified Protein Derivative-Negative Adults CLINICAL AND VACCINE IMMUNOLOGY, Nov. 2010, p. 1763–1771

75. Purified Vero cell Rabies vaccine-
Next Generation [PVRV NG]
 No component of human/ animal origin,
 Very low residual DNA content
 No risk of contamination with
non-conventional transmissible agents.
 Phase II clinical trial demonstrated
comparability of Verorab and PVRV-NG as regards to
safety and immunogenicity
 Phase III in 816 participants aged ≥10 years demonstrated
the immunogenic non-inferiority of PVRV-NG compared
with Verorab after three doses of postexposure regimen
Li R et al, A next-generation, serum-free, highly purified Vero cell rabies vaccine is safe and as immunogenic as the reference vaccine Verorab® when administered
according to a post-exposure regimen in healthy children and adults in China. Vaccine. 2013 Dec 5;31(50):5940-7. doi: 10.1016

76. Cholera
Dukoral Shanchol
Killed whole cells plus
recombinant B subunit
Killed whole cells only
For persons >= 2 yrs For persons >= 1 yrs
2 doses given 7 – 42 days apart 2 doses given 14 days apart
Booster every 2 yrs Booster every 2 -3 yrs
Protection for 2 yrs Protection for 3 yrs
May 2014: Two complete doses of Shanchol protected
individuals by 86 percent during a recent cholera outbreak
in Guinea

77. Live Oral Cholera Vaccine VA 1.4
 National Institute of Cholera & Enteric Diseases,
 Kolkata
 Live attenuated single dose oral vaccine developed by isolating a
'Vibrio cholerae O1 El Tor' strain
 Genetically engineered to produce only the immunogenic B subunit
 Phase I trial in 87 subjects revealed safety and 67% seroconversion
on day 7 after the first dose
 Phase II trial will be started soon
2main advantages:
 Single dose confers higher levels of protection
 No gene that produces the cholera toxin (gene for subunit A)
Suman Kanungo et al. Safety and Immunogenicity of a Live Oral Recombinant Cholera Vaccine VA1.4: A Randomized, Placebo Controlled
Trial in Healthy Adults in a Cholera Endemic Area in Kolkata, India

78. Rotavac rotavirus vaccine
 India’s first indigenously developed oral Rotavirus
Vaccine
 live attenuated rotavirus strain 116E
 Phase III clinical trial in 6,799 infants revealed significant
reduction in severe rotavirus diarrhoea by 56% during
the first year of life, with protection up to 2 yrs
 Three doses at the ages of 6, 10, and 14 weeks
 Well tolerated when co-administered with UIP vaccines
 Approval pending
John J, Sarkar R, Muliyil J, Bhandari N, Bhan MK, Kang G. Rotavirus gastroenteritis in India, 2011-2013: revised estimates of disease burden and potential
impact of vaccines. Vaccine. 2014 Aug 11;32 Suppl 1:A5-9

79. Therapeutic Cancer Vaccines
 In 1891, Dr. William Coley: first attempt to
stimulate the immune system for improving a cancer
 Intratumoral injections of inactivated Streptococcus pyogenes
and Serratia marcescens (Coley's Toxin)
Allogeneic
tumour
vaccine
Autologous
tumour
vaccine

80. Tumour type Infectious agent
Cervical cancer Human papilloma virus
Head & neck cancer Human papilloma virus
Hepatocellular carcinoma Hepatitis B & C virus
Burkitts lymphoma Epstein-Barr virus
Post transplant
lymphoproliferative disease
Epstein-Barr virus
Nasopharyngeal carcinoma Epstein-Barr virus
Gastric cancer Helicobacter pylori
Primary effusion lymphoma Human herpes virus 8
T- cell leukemia Human T-cell leukemia virus 1, 2
Kaposi’s sarcoma Kaposi’s sarcoma-associated
herpes virus
Infections associated with cancer development

81. Ca Prostate: PROVENGE® (Sipuleucel-T)
 FDA approval on 29 April 2010.
 Autologous cellular immunotherapy
 Treatment of asymptomatic or minimally symptomatic
metastatic castrate resistant (hormone refractory) prostate cancer.
 3 doses at 2-week intervals increased median survival by 4.1
months in phase 3 RCT
 Each dose contains minimum of 50 million autologous CD54+cells
activated with GM-CSF
Adverse events reported: chills, fatigue, fever, back pain, nausea,
joint ache, and headache
Cheever MA, Higano CS, PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine.Clin Cancer Res 2011 Jun 1;17(11):3520-6.
doi: 10.1158/1078-0432.CCR-10-3126. Epub 2011 Apr 6.

82.  Recombinant vaccinia virus expressing PSA
 Phase 3 PROSPECT trial is ongoing
 Randomized, placebo-controlled, multi-centre, global 3-arm
trial of PROSTVAC in men with asymptomatic or minimally
symptomatic, metastatic, castrate-resistant prostate cancer.
Ca Prostate: rV-PSA (Prostvac)
Ravi A Madan,Philip M Arlen, Mahsa Mohebtash, James W Hodge and James L. Gulley*Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer
Expert Opin Investig Drugs. Jul 2009; 18(7): 1001-1011.doi: 10.1517/13543780902997928

83. Breast Cancer: Neuvax (E75)
 Nonapeptide derived from the extracellular domain of the HER2
protein
 Two Phase II trials in 195 women with HER-2 positive breast
cancer showed a 48% reduction of relative risk of recurrence
 Phase 3 PRESENT trial (Prevention of Recurrence in Early-Stage
Node-Positive Breast Cancer with Low to Intermediate
HER2 Expression with NeuVax™ Treatment) is ongoing
 Two stages of administration:
 An intradermal injection once per month for six months (6
total)
 Booster shots once every six months for 30 months (5 total)Milani A, Sangiolo D, Aglietta M, Valabrega G. Recent advances in the development of breast cancer vaccines. Breast Cancer (Dove Med Press). 2014 Oct 14;6:159-68

84. Melanoma: POL-103A vaccine
 Contains multiple melanoma-associated antigens that are shed
from 3 human melanoma cell lines
 Two Phase II trials demonstrated strong efficacy in terms of
significantly improved recurrence-free survival and overall
survival with excellent safety profile
 Currently, Phase III MAVIS trial (Melanoma Vaccine in Stage IIb,
IIc, and III Melanoma Patients) designed to enrol a total of 1059
patients is ongoing
https://clinicaltrials.gov/ct2/show/NCT01546571 accessed on 15.1.15

85. Bladder cancer: CG0070 vaccine
 Type of Oncolytic virus therapy
 Stimulates cytokine GM-CSF to enhance anti-tumour
immune response
 Phase 1 study with Intravesical CG0070 demonstrated safety
and tumour response rate 48 – 77 %
 Phase 2/3 pivotal BOND (Bladder Oncolytic virus for Non-
muscle invasive bladder cancer Disease) trial of intravesical
CG0070 for non-muscle invasive bladder cancer patients is
ongoing
Burke JM et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer.
J Urol. 2012 Dec;188(6):2391-7

86. Ongoing phase III trials
Cancer Vaccine & trial Vaccine type
Renal cell
cancer
AGS-003
(ADAPT trial)
DC/APCs
Glioblastoma DCVax®-L
Rindopepimut (ACT IV)
DC/APCs
Peptides/proteins
Epithelial
ovarian cancer
Cvac
(CANVAS trail)
DC/APCs
Pancreatic
cancer
GV1001
(PRIMOVAX)
Peptides/proteins
NSCLC Stimuvax (START trial)
TG4010
Peptides/proteins
Virus vectors
SCCHN INGN 201 Virus vectors

87. Lessons from cancer vaccine trials
 Cancer vaccines have demonstrated minimal toxicity in
all clinical trials with little evidence of autoimmunity
 Patients who have received less prior chemotherapy
are generally more responsive to vaccines
 Technical and developmental challenges
 Challenges exist for developing combination therapy that
incorporates cancer vaccine with established cancer
therapeutics
Wolchok JD et al, Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res, 2009 Dec 1;15(23):7412-
20. doi: 10.1158/1078-0432.CCR-09-1624.

88. Key factors driving vaccine market in India
 Relatively low cost of manufacturing
 Reasonable R & D expenditure
 Leading edge technology/Combination vaccines
 Abundant skilled manpower
 Huge demand
 High potential for the new vaccines
Funding, slow regulatory approval and
dependence on government persist as
challenges for vaccine development in India

89. From global perspective,
 Rotavirus vaccine
 Pneumococcol conjugate
 HPV vaccine
From industry’s perspective,
Focus is shifting towards DNA and
recombinant vaccines
To conclude,