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Recent advances in Vaccine DevelopmentDr. Mansij BiswasDr. Pooja VaidyaDr. Anup Petare

Department of Pharmacology & TherapeuticsSeth GS Medical College & KEM HospitalPrevention is better than cure

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

English physician Edward Jenners use of the term variola vaccinae (means small pox of the cow in latin), adapted from the Latin word vacca meaning cow, in 1796.Jenner published a paper in which he mentioned that people could be protected from the deadly disease smallpox by the prick of a needle dipped in the pus from a cowpox boil.

Milestones in vaccine development1798: Edward Jenner invented smallpox vaccine

1885: Louis Pasteur developed the first vaccine to protect humans against rabies

1927: BCG vaccine recognized

1955: Dr. Jonas Salks inactivated polio vaccine licensed, beginning the decline of polio worldwide.

1908- BCG- albert calmette, camille guerin1963 : 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 development2003: 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) approved2009: Influenza A (H1N1) vaccine approved

Milestones in vaccine developmentThey help healthy people stay healthyBenefit 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?Center for disease control & prevention7Concept of vaccination:

MOA: When inactivated disease-causing microorganisms enter the body, they initiate an immune response. This response mimics the bodys natural response to infection. But unlike disease-causing microorganisms, vaccines are made of components that have limited ability, or are completely unable, to cause disease.8 Types of vaccinesWhole-Organism VaccinesKilled (Pertussis, Cholera, Rabies, Influenza)Live Attenuated (BCG, OPV, Measles, Mumps, Rubella)Purified Macromolecules as VaccinesToxoids (Diphtheria, Tetanus)Cellular fractions:Capsular polysaccharides (pneumococcal)Cell wall polysaccharides (meningococcal)Surface antigens (Hepatitis B polypeptide)Combinations (DPT, MMR) Newer approaches:Recombinant vaccineDNA vaccine Multivalent Subunit Vaccines According to microorganism Bacterial (BCG, Cholera, Typhoid, toxoids) Viral (OPV, MMR, Rabies, Hepatitis) Rickettsial (Epidemic typhus)

According to indication Preventive Therapeutic

10Basic steps of vaccine productionQUALITY CONTROL AND LOT RELEASEUpstream processingDownstream processing

Future prospectsUse 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 vaccineIncluding in the vaccine only those subviral components needed to stimulate protective antibody, minimizing occurrence of adverse reactionsUse 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 VLPUse 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)Development of edible vaccines where transgenic plants synthesizing antigens from pathogenic viruses provide new cost effective way of vaccine deliveryUse 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 proteinAdministration 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 Live Bacterial Vector - capacity of bacteria to colonize and infect the intestinal mucosa led to development of effective vectors for the oral delivery of vaccine antigen eg. Salmonella which can be attenuated making it avirulent but preserving invasivenessParticulate Formulations - act to protect vaccine antigens against degradation and enhance their uptake by the immune systems Mucosal Adjuvants - most potent and widely used adjuvants are cholera toxin (CT) and the closely related E. coli heat-labile enterotoxin (LT)transcutaneous immunization - combines vaccine antigen with heat-labile enterotoxins from E coli as an adjuvant that is applied in a patch to the epidermis of skin pretreated by mechanical disruption of the stratum corneumliquid jet injection and epidermal powder immunization uses high pressure to blast the liquid or powder through the stratum corneum and into the body microneedle-based injection system - microneedle that penetrates 1.5 mm into the skin is used to deliver vaccine to the dermisReverse 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. 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.

OldNewProtective immunity in children under two years of age. NoYesCreate a long-lasting memory of the pathogenNo YesHerd immunity (e.g. Pneumococcus)NOYesDNA Vaccines: a promising futureDNA 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

Advantages of DNA Vaccines

Cheaper and easier to produceLarge rapid GMP manufacturing capabilitiesNo need to handle infectious pathogens during productionSaferCan elicit both humoral & cell mediated immunityStable 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 vaccineAbility to immunize against multiple antigens and/or PathogensNonviral and no induction of anti-vector immunity

Vaccine DevelopmentProcess developmentClinical developmentAssay developmentBulk manufacturing

Product finishingPhase I

Phase II

Phase IIIPurity

Potency

StabilityDiscoveryThe development process for vaccines is unique. Given the importance of safety with biologics, the vaccine industry is highly regulated.Process development: to produce an economically viable vaccine, consistently, in a manner that satisfies regulators;Clinical development: to demonstrate the safety and measure the protective effect of the vaccine in humans;Assay development: to develop the appropriate tests to ascertain the purity, potency and stability of the vaccine under developmentProcess development is further divided into bulk manufacturing and product finishing. Bulk manufacturing involves the culture of live microorganisms, followed by separation and purification of the desired antigen. Finishing involves the formulation with either adjuvant and/or stabilizer and the filling of vials or syringes.Assay development is required because the vaccine candidate will be novel and will therefore require specific tests to identify it and characterize the product to the satisfaction of the regulators.22

Nature, 463469 (26 May 2011); A 2020 vision for vaccines against HIV, tuberculosis and malaria

1902: Biologics Control Act/ Virus-Toxin Law

1997: FDA Modernization Act

Clinical developmentPre-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

After being thoroughly tested in an animal model, vaccine candidates that are found to be safe and induce immunity can advance to testing in humans. The Center for Biologics Evaluation and Research (CBER) of the US Food and Drug Administration (FDA) is the federal regulatory agency charged with ensuring the safety, purity, and efficacy of vaccines.In FDAMA, Expedited approval mechanisms for life-threatening conditions and the use of surrogate end points in clinical trials were authorized Pre-IND stageIdentification of components and antigens Preclinical testingto rule out overt toxicityidentify potential toxic effects that might occur during the clinical trial and reversibility of the toxicityRequirements for preclinical toxicity studies depend on,vaccines potential risk/benefit consideration target populationavailable clinical data from the use of related productsavailability of animal models

Investigational New Drug Stage Phase ISafety & immunogenicity studyPhase IISafety/ Dose ranging studyPhase IIILarge scale safety/efficacy studyin small numbers (e.g. 20-100) of healthy adults, apprx 1 yearto 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.There are typically 3 successive phases in the clinical evaluation of vaccine products under the IND regulations

Investigational New Drug Stage Phase IIInitial trials examining safety, effectiveness (immunogenicity) dose range & pharmacokineticsIn several hundred volunteers forming the target groups, like, children, adults or those at risk of exposure to pathogens1-3 yearsTo obtain preliminary estimates on rates of common adverse eventsEarly Phase II is usually an exploratory trialLate Phase II is known as pivotal efficacy study Investigational New Drug Stage Phase IIIprovides the critical documentation of the vaccines safety and effectiveness needed to,evaluate the risk/benefit relationship to support licensuretypically enrol several thousand subjects.3-5 yearsManufacturing reproducibility is typically addressed by evaluation of lot consistency and ensuring process validationVaccine efficacy:Reduction in incidence of the disease after vaccination compared to the incidence that prevailed before vaccination

Vaccine effectiveness:Provides information of protective rate conferred on a given population Vaccine licensure based on demonstration of safety, immunogenicity, and efficacybased on ability to manufacture product in a consistent manner

Biologics license application (BLA)Data derived from nonclinical and clinical studiesDescription of manufacturing methodsCompliance with GMP requirementsDocumentation of all raw materials usedData establishing stability of the productSamples representative of the productDescription of equipment and facility of each location involved in the manufactureThe sponsor submits the BLA to the director of the CBER Office of Vaccines Research and Review

Lot-Release Testing includes,

Sterility, purity: detects the presence of bacterial or fungal contaminantsGeneral safety: detects toxicityIdentity: verifies that a product induces specific antibodies after vaccinationPotency: verifies immunogenicity, antigen content, or chemical composition Tests for removal of process contaminants Pyrogenicity: detects the presence of fever inducing substancesAlso, constituent materials such as diluents and preservatives must meet standards for sterility Post approval stage It is mandatory for all licensed vaccines undergo appropriate lot testing before release30Extended stability studiesTropical countries like IndiaMaintenance of cold chainLot 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 Post approval stage Post marketing SurveillanceNecessary component of vaccine-safety monitoringDone in large populations over longer periods of time Important objectives:to monitor increase in known reactionsto identify rare adverse reactions not detected during pre-licensure studies

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 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 scaleImmunogenicity data can easily be used to extrapolate efficacy results when the immune response correlates with vaccine induced immunityDesigned 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 extrapolatedFritzell B; Bridging studies; Dev Biol Stand.1998;95:181-8.

Only comparison of sera with historical control from an efficacy trial is warranted, and no clinical trial need be undertakenSanofi Pasteurs A(H1N1) vaccine Panenza in India 2010 Special concernsA 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.

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

Need for development of newer vaccines !!No effective vaccine available for major mortality causing diseases like Malaria, TB and AIDSNeed for effective, potent & stable vaccinesMinimal/No adverse reactionsNew Delivery Techniques for better compliance Lower costProtect against more diseases & sustained protectionEmerging and Re-emerging DiseasesEra of progressing antibiotic resistanceCertain Pandemic Non-Infectious DiseasesRecent advances

Vaccine422010 Menveo (meningitis vaccine)Quadrivalent conjugate vaccine containing theNeisseria meningitidisserogroups A, C, Y and W-135For active immunization to prevent invasive meningococcal disease in persons 11 to 55 years of ageSingle 0.5 ml I.M. injectionFDA approval was based on demonstration of efficacy in randomized, multicentre, active controlled clinical trial conducted in the 3539 subjectsAdverse events: pain at the injection site, headache, myalgia

In 2010, Approved in February 2010

The efficacy of Menveo has been inferred by measuring the production of serogroup-specific anti-capsular antibodies with bactericidal activity. Serum bactericidal activity (SBA) was measured using human serum as the source of exogenous complement (hSBA). The hSBA was the original correlate of protection against meningococcal disease.Safety and effectiveness of Menveo have not been evaluated in immunocompromised persons. If Menveo is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the expected immune response may not be obtained.2010 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

Acute lower respiratory infections are responsible for about two million deaths per year and a large proportion of these are caused by Streptococcus pneumoniae. Currently licensed pneumococcal vaccines like Pneumovax 23 are based on the generation of antibodies to the pneumococcal polysaccharide antigens, of which there are more than 90 different types. But, Polysaccharide vaccines are not very effective at protecting young children, do not create long-lasting immunity, and do not confer a "herd effect"PCV 7 was the first conjugate vaccine amongst pneumococcal vaccineAnd now in February 2010, US FDA approved a conjugate vaccine Prevnar 13Vaccine schedule: For Infants and Toddlers: Four-dose series 0.5ml I.M. at 2, 4, 6, and 12-15 months of ageFor 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.

2010 Prevnar 13 (Pneumococcal 13 valent Conjugate Vaccine)

Unvaccinated Children 7 Months of Age are children who are beyond the age of the routine infant schedule and have not received Prevnar or Prevnar 13

Menactra (Meningococcal Polysaccharide Diphtheria Toxoid Conjugate Vaccine)2011Invasive meningococcal disease by Neisseria meningitidis serogroups A, C, Y and W-13511-55 years2-10 years9 months200420072011Safety evaluated in 4 clinical studies in 3700 participantsAdverse events: injection-site tenderness and irritability9 - 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.For prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135.In 2004 FDA approved Menactra for active immunization of adolescents and adults 11-55 years of age.In 2007, Age indication was expanded to include children 2-10 years of age.In 2011, FDA approved the use of Menactra in children as young as 9 months

2011 Other official recommendationsZostavax, live attenuated vaccineApproved for use in 50 to 59 years of ageBased on a multicenter study in 22,000 people, 50-59 yrs, which showed that Zostavax reduced the risk of developing shingles by 70 percentIn January 2011, Menveo approved for use in children 2 - 10 years Based on 2 RCTs (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

Zostavax, live attenuated vaccine, licensed in the US, is a preparation of the Oka/Merck strain of varicella zoster virusZostavax was originally approved in May, 2006, for the prevention of herpes zoster in individuals 60 years of age and older.

Zoster vaccine should be administered as a single 0.65-mL dose SC in the deltoid region of the upper armbooster dose is not licensed for the vaccinevaccine should not be injected intravascularly or intramuscularly MenHibrix (Conjugate vaccine)2012For 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 ageSafety demonstrated in 6767 subjects and Immunogenicity demonstrated in 2925 subjects ADR: Injection site pain, irritability, fever and loss of appetite In 2012, 11 vaccines were approved, out of which GSK's Menhebrix is the only non-influenza vaccine, rest all are influenza vaccines. It was approved for active immunization ..

Vaccines for Hib began flooding the market back in the 1980s. But MenHibrix has an edge because healthcare providers can give it to patients as young as 6 weeks old.

Flucelvax (Influenza vaccine)2012Inactivated trivalent cell-culture-derived vaccine against A (H1N1, H3N2) & B subtypes For active immunization in adults aged 18 years and olderSingle 0.5 ml I.M. injectionThe 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 rateImmunogenicity confirmed in 3 clinical studies in 1353 subjectsAdverse events reported: injection site reaction, headache, fatigue

Approved November 2012 for the prevention of influenza disease caused by influenza virus subtypes A and type B

Fluarix Quadrivalent influenza vaccine2012First intramuscular Quadrivalent influenza vaccine3 years of age and olderRecommended dose:3 8 years: Two doses 0.5 ml each I.M., at least 4 weeks apart9 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

Thereafter, Fluarix Quadrivalent vaccine against H1N1, H3N2 and B subtypes was approved by the FDA on December 14, 2012, for use in persons 3 years of age and older

2013Flublok (seasonal influenza vaccine)Trivalent recombinant vaccineFor 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 immunogenicityAdverse events noted were injection-site reaction, headache, fatigue, myalgia

Received accelerated approval in Oct 2014 for use in persons 50 years of age and olderThen in 2013,Flublok ..another trivalent recombinant vaccine was approved in January 2013The vaccine contains recombinant HA proteins of the three strains of influenza virus, which function as antigens which induce a humoral immune responseFDA approval of Flublok was based on a RCT in 4,648 healthy adult subjects revealed HAI antibody responses were seen in 78%, 81%, and 52% of H1, H3, and B component recipients

Fluzone Quadrivalent influenza vaccine2013Inactivated Quadrivalent vaccine 6 months of age and olderDose:6 months to 35 months: 2 doses of 0.25 ml each I.M 4 weeks apart36 months to 8 years: 2 doses of 0.5 ml each I.M 4 weeks apart9 years and older: Single I.M 0.5 ml injectionApproval based on immunogenicity studies in 1419 children, 6 35 months of age and in 2101 children, 3 to 8 years of ageAdverse reactions: Injection site reactions, irritability, abnormal crying, myalgia, fever and vomiting

Also in 2013, inactivated Quadrivalent influenza vaccine was approved for use in 6 months old infants2014TRUMENBA (Meningococcal Group B Vaccine)Approved on October 29, 2014 via accelerated approvalFirst vaccine licensed in the US to prevent invasive meningococcal disease byNeisseria meningitides serogroup B in individuals 10 - 25 years of age.Approval was based on demonstration of immune response in 3 randomised trials in 2800 adolescentsThree doses of 0.5 mL each by intramuscular injection at 0, 2 and 6 monthsADR: Pain at injection site, headache, myalgia and fatigueGardasil 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 11Girls and women 9 - 26 years of age0.5-mL intramuscular injection at 0, 2 months, 6 monthsAdded protection against five additional HPV types 31, 33, 45, 52 and 58RCT 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

2014Approved in December, 2014 for prevention of, cervical .In Girls and women 9 26 yrs of age

Gardasil 9 covers nine HPV types, five more HPV types which cause approximately 20 percent of cervical cancers and are not covered by previously FDA-approved HPV vaccines.

The safety of Gardasil 9 was evaluated in approximately 13,000 males and females.542014 Afluria needle free influenza vaccine Trivalent inactivated influenza vaccine 5 years of age and olderSafety & efficacy demonstrated in a RCT conducted in 15,044 subjects Immunogenicity established in an RCT in 832 subjects, 5 to 17 yrsDose:5 8 yrs: 1 or 2 doses of 0.5 ml each I.M, at least 4 weeks apart9 yrs and older: Single 0.5 ml dose via needle-free delivery system approved by the FDAADR: Pain at injection site, headache, myalgia and fatigue

Recommended for use in children 5 years and older Fluzone Intradermal QuadrivalentInactivated Quadrivalent vaccine against subtype A (H1N1 & H3N2) & B virusApproved for use in persons 18 - 64 years of ageSingle 0.1 mL dose for intradermal injectionApproval based on Immunogenicity studies in 2249 participantsAdverse reactions: injection-site reactions, headache and myalgia

2014

Approved on 8 December, 2014LipOsomes/ Nanosomes ??????????56Vaccines in pipelinePreventive TherapeuticHIV vaccineUrgent global priority An ideal HIV vaccine goal: Sterilizing immunityRealistic goal: to prevent viremia

More than 20 million people have died of AIDS since the first clinical cases became apparent in 1981.The HIV epidemic is outpacing even pessimistic predictions from previous years, indicating that efforts to limit HIV spread have so far been largely ineffective.An HIV vaccine is an urgent global priorityAn ideal HIV vaccine would prevent HIV infection in an exposed individual through eliciting an effective immune response, a concept known as sterilizing immunity. More realistically, an effective HIV vaccine would limit HIV replication, which would delay the progression to AIDS and would substantially reduce the risk of HIV transmissionSeveral candidate vaccines have been tested in human trials and efforts to develop an HIV vaccine are increasing. But, the 3 major scientific challenges in development of vaccine against HIVThe immunological correlates of HIV/AIDS protection is not knownThe genetic variability of HIVThe lack of good animal models58HIV vaccineCandidate VaccineComponentFirst generationBased on envelope proteins especially gp120Second-generationLive vectors (such as canarypox) or naked DNA coding for different HIV genes

Third-generationRegulatory 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

A major crossroads for First generation recombinant gp120/160-based HIV vaccine trials was reached in 1994. These vaccines were safe and well tolerated and elicited CD4+ T lymphocyte response, but, did not elicit CD8+CTL and were not able to induce neutralizing antibodies was a difficult unsolved problem. Then, a panel of experts in the field concluded that gp120 vaccination had exerted no detectable influence on HIV replication.Then, second generation Live viral vectors represent a promising approach, a subset of these also developed CD8+ CTL response. But, the CTL responses were dependent on dose of the vector injected and the limiting factor was the inability to generate high titre stocks in large scale manufacturing.Then, the third generation vaccines .59HIV vaccine

This is a summary of the currently ongoing trials,Of these, ALVAC and AIDSVAX are in the most advanced stages of development.

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 HIVs envelope protein correlated with lower infection rates among those who were vaccinated.HIV vaccine RV144 trial, concluded in 2009 and involved more than 16,000 adults. It used two vaccines in combination one as the prime vaccine and the second as a boost. The boost AIDSVAX vaccine was the investigational vaccine which was used in the earlier VAX003 trial in 2003, which was found to be ineffective.Later, the researchers found that participants in the RV144trialwere more likely to have HIV-specific IgG3 antibodies, compared to individuals in the VAX003 trial. This HIV-specific IgG3 response correlated with decreased infection risk, but the effect waned over time61HIV vaccine RV 305 trialOngoing Phase IIB trialTo assess safety and tolerability of late boost regimens of AIDSVAX alone, ALVAC alone, or ALVAC/AIDSVAX combination in HIV-uninfected participants from RV 144Goal of the secondary boost is to try to extend and increase the immune response seen in RV144

Ongoing Phase I trialTo gather more immunogenicity data in 360 new volunteers using R144 regime

HIV vaccine RV 306 trialA small clinical study, RV305, was started in April 2012 in Thailand to evaluate re-boosting in volunteers who participated in the RV144 study.62

tgAAC09A recombinant adeno-associated virus type 2, HIV-1 subtype C vaccineDoes not contain HIV virusPhase I trial in 80 HIV-uninfected healthy volunteersshowed that vaccine was safe, well-tolerated, and modestly immunogenicPhase II, Placebo-controlled, Double-blind, Dose-escalation Trial to Evaluate Safety and Immunogenicity is completed in 2012Trials to evaluate higher doses and boost injections is ongoing in Africa.National AIDS Research Institute (NARI), Pune with ICMR came up with the HIV Vaccine called tgAAC09. Phase I studies: 50 participants in Europe and 30 in IndiaPhase II study completed but results are not available.

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 MontagnierLuc Montagnier, French virologist who won the Nobel Prize in 2008 for discovering the AIDS virus, said once on Vaccine for AIDS, that64

Zaire species of ebolavirus is responsible unprecedented 2014 epidemic of Ebola Virus Disease. Thus it prompted the international response to accelerate the availability of a preventive vaccine

Ebola virus disease (EVD)cAd3Vectored vaccines: Ebola virus glycoprotein is presented in a replication-incompetent chimpanzee adenovirus 3Phase 1, dose-escalation trial in 20 healthy adults with bivalent form and in 60 healthy adults with the monovalent form is ongoingrVSVVectored 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 . The two leading candidates are vectored vaccines.. in which the Ebola virus glycoprotein is presented in a .replication-incompetent chimpanzee adenovirus 3 / cAd3 or a replication-competent vesicular stomatitis virus/ rVSV. Both vaccines have shown 100% protection in nonhuman primates.. at 4 to 5 weeks after single doses were administered ..and have now been rushed into phase 1 trials Several other vaccine candidates are at earlier, preclinical stages in the development pipeline.Rvsv: The government of Canada has donated. 800 vials of rVSV to the WHO,Discussions about expanding phase 1 trials to European and sub-Saharan African sites are at an advanced stage.

66Malaria

Pre-erythrocytic vaccines: prevent clinical manifestationErythrocytic vaccines:prevent invasion of RBC by merozoites & speed parasitized RBC clearanceDecrease the symptom severityTransmission blocking vaccines:blocks human to human transmissionMalaria is endemicinmorethan100countries. and eachyear,malariainfects300500millionpeople. (morethan1milliondeaths) .Pre erythrocytic vaccines:.. Prevents clinical manifestation.

Erythrocytic vaccines - prevent the invasion of RBC by merozoites, and.. speed the parasitized RBC clearance therefore avoid their sequestration in the microvasculature, does not interfere with infection but decrease the severity of symptoms

Transmission blocking vaccines.. - benefit the community where vaccinated individuals live by blocking human to human transmission

MalariaCircumsporozoite protein (CSP)Merozoite surface protein (MSP) Apical membrane antigen 1 (AMA-1)MultipleAntigenPeptide(MAP)VaccinesEffective immunityCurrently in preclinical stagesBabitaMahajan et al. MultipleAntigenPeptideVaccines againstPlasmodiumfalciparumMalaria infectionandImmunity2010:70(11):46134624More than 50% of the Malarial vaccines in active development today are based on just three antigens, Circumsporozoite protein , Merozoite surface protein, Apical membrane antigen 1. Ateamofscientistsledbyresearchersfrom..Centre for Biologics Evaluation and Research designed,synthesized,andtestedinmice.. multipleantigenpeptideMAP vaccinesagainstmultiplelifecyclestagesoftheP.falciparummalaria

MalariaRTS,S/AS02APre-erythrocytic subunit vaccineFusion of surface CSP antigen with the HBsAg, formulated with the AS02 adjuvant systemAcceptable side-effect profile and immunogenicity confirmed in children 6 weeks of age or olderPhase 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):329-36Currently, malaria vaccine in the most advanced stage of development is RTS It is . Pre-erythrocytic subunit vaccine.Fusion of surface Circumsporozoite protein antigen with the HBsAg, formulated with the AS02 adjuvant system..It has Acceptable side-effect profile ..and immunogenicity confirmed in children 6 weeks of age or olderPhase 3 trial is ongoing in 15,460 children in two age categories : 6 to 12 weeks of age and 5 to 17 months of age, it showed protection against clinical and severe malaria up to 18 months after vaccination..

And GSK now intends to submit a regulatory application.. to the European Medicines Agency. and the world's first anti-malaria vaccine may be approved for use within two years.

DengueCYD-TDVLive attenuated tetravalent vaccineVaccine efficacy of 57%: Phase III study in 10,275 children aged 2 to 14 years in 5 countries in the Asia-Pacific revealed3 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 & immunogenicA second Phase III trial: ongoing in 31000 subjects of Latin AmericaDa 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

CYD-TDV it is Live attenuated tetravalent dengue vaccine ..Vaccine efficacy of 57 % was revealed ..in Phase III study in 10,275 children aged 2 to 14 years in 5 countries in the Asia-Pacific ..with more than 75% protection against DENV 3 and 4 serotype,.. 50% against DENV 1 and 35% against DENV 2 strain.3 doses were 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 to be safe & immunogenicAlso, there was No increase in SAE in the trial during the two years following administration of vaccineA second Phase III trial: is ongoing in 31000 subjects in Latin America

Tuberculosis remains a major global health problem. While BCG is the most widely used vaccine in the world, it has not successfully eliminated the disease due to its limited efficacy. So, development of new vaccines remains the cornerstone to reaching global elimination.

TuberculosisNonliving vaccines: purified antigen subunit vaccines and DNA vaccinesLive mycobacterial vaccines: attenuated strains or BCG strainsUse of viral vectors such as adenovirus or vaccinia virus

approaches which have been used to produce new vaccines Nonliving vaccines: purified antigen subunit vaccines and DNA vaccines

Live mycobacterial vaccines, which include rationally attenuated strains of M. tuberculosis or BCG strains.. viral vectors used such as adenovirus or vaccinia virus

TuberculosisBoosting BCG with MVA85A Modified Vaccinia Ankara virus expressing antigen 85AInduces higher levels of both antigen specic CD4+ T and CD8+ T cells when used together with BCGPhase I clinical trials showed excellent safety profileA 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 tuberculosis in clinical trials. Tuberculosis (Edinb). 2005 Jan-Mar;85(1-2):47-52.Antigen 85A is considered a leading candidate antigen for inclusion in a TB vaccineModified Vaccinia Ankara is attenuated strain of vaccinia virus. passaged more than 500 times though chick embryo broblasts.It Induces higher levels of both antigen specic CD4+ T. and CD8+ T cells when used together with BCGPhase I clinical trials showed excellent safety profile.A randomised, placebo-controlled phase 2b trial in 2,797 infants revealed 17. 3% vaccine efficacy against tuberculosis.

TuberculosisBoosting BCG with Mtb72F/AS02AFusion protein derived from Mtb39A & Mtb32A antigens with AS02A adjuvant system

Under development for:Prevention of primary TB infection in young children of highly endemic areasAs an adjunct to treatment for TB in adolescents & adults.

Phase I study in PPD-negative TB-nave, 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 Puried Protein Derivative-Negative Adults CLINICAL AND VACCINE IMMUNOLOGY, Nov. 2010, p. 17631771Mtb 72F/ASO2A is Fusion protein .derived from Mtb39A and Mtb32A antigens with AS02A adjuvant system

It is Under development for: .Prevention of primary TB infection in young children in highly endemic areas.As an adjunct to treatment for TB in adolescents and adults

Phase I study in Purified Protein Derivitive-negative TB-nave, healthy adults revealed safety and immunogenicity in healthy adults .when given in as 0-, 1-, and 2-month schedule

Currently Phase II trial in healthy PPD-positive volunteers aged 18 to 50 years is ongoing

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

Two rabies vaccines are currently manufactured.. : a human diploid cell vaccine Imovax and purified Vero cell rabies vaccine VerorabAnd the vaccine in development is the purified Vero cell rabies vaccine (PVRV Next Generation [PVRVNG]The vaccine is prepared from the inactivated PitmanMoore strain, but without any component of human or animal origin .has Very low residual DNA content.. No risk of contamination with non-conventional transmissible agents eg. associated with Bovine Spongiform Encephalopathy and scrapie)..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

CholeraDukoralShancholKilled whole cells plus recombinant B subunitKilled whole cells onlyFor persons >= 2 yrsFor persons >= 1 yrs2 doses given 7 42 days apart2 doses given 14 days apartBooster every 2 yrsBooster every 2 -3 yrsProtection for 2 yrsProtection for 3 yrsMay 2014: Two complete doses of Shanchol protected individuals by 86 percent during a recent cholera outbreak inGuinea

Injectable, killed whole-cell cholera vaccines were developed in the late 19th century and used widely. However, clinical trials in India, Bangladesh, Philippines and Indonesia found that the vaccines conferred only modest protection (about 50%) for less than 6 months.. Also, these were associated adverse events. New understandings yielded insight that protective immunity is best generated by oral administration of cholera antigens.Currently, Dukoral and Shanchol are the licensed and pre-qualified vaccines available ..Dukoral...Killed whole cells plus recombinant B subunit For persons >= 2 yrs 2 doses given 7 42 days apart.. Booster for every 2 yrs it gives Protection for 2 yrsShanchol contains Killed whole cells only.given to persons >= 1 yrs 2 doses are given 14 days apart.. Booster given every 2 -3 yrs giving protection for 2-3 yrs

According to a study published in the NEJM on may 2014, two complete doses ofShanchol protected individuals by 86 percent during a recent outbreak inGuinea

Live Oral Cholera Vaccine VA 1.4National Institute of Cholera & Enteric Diseases, KolkataLive attenuated single dose oral vaccinedeveloped by isolating a 'Vibrio choleraeO1 El Tor' strainGenetically engineered to produce only the immunogenic B subunitPhase I trial in 87 subjects revealed safety and 67% seroconversion on day 7 after the first dosePhase II trial will be started soon

2 main advantages:Single dose confers higher levels of protectionNo 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 ControlledTrial in Healthy Adults in a Cholera Endemic Area in Kolkata, IndiaNational Institute of Cholera & Enteric Diseases, Kolkata.. developed a live attenuated single dose oral cholera vaccine called VA1.4 .. It has two main advantages over other counterparts .Single dose confers higher levels of protectionAnd No gene that produces the cholera toxin that is gene for subunit A

Rotavac rotavirus vaccine

Indias first indigenously developed oral Rotavirus Vaccinelive attenuated rotavirus strain 116EPhase 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 yrsThree doses at the ages of 6, 10, and 14 weeksWell tolerated when co-administered with UIP vaccinesApproval 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:A5-9Globally 4,53,000 deaths occur per year from rotavirus gastroenteritis and >90% of the estimated global rotavirus deaths occur in low income countries in Africa and Asia.Rotashield vaccine was in market since 1999, .but was withdrawn as the risk of intussusception was found to be 22 folds higher.Thereafter, Pentavalent vaccine Rotateq (RV5) .and monovalent Rotarix vaccine (RV1) .were approved. But, there have been post marketing reports of Intusseption, Kawasakis disease and virus shredding (Viral gastroenteritis due to shredding). Currently , Government of Indias Department of Biotechnology. and Bharat biotech developed ROTAVAC, Indias first indigenously developed Rotavirus Vaccine.The cost of this vaccine will be Rs. 54/dose in case of approvalIt is live attenuated rotavirus strain 116EIn 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 week given.It is Well tolerated when co-administered with other vaccines.Approval pending so the question now is ...Will Rotavac find its place in the National Immunization program in India?Therapeutic Cancer Vaccines

In1891,Dr.WilliamColey:firstattempttostimulatetheimmunesystemforimprovingacancer

IntratumoralinjectionsofinactivatedStreptococcuspyogenesandSerratiamarcescens(Coley's Toxin)Allogeneic tumour vaccineAutologous tumour vaccineCancer is a major cause of morbidity and mortality worldwide. The global incidence of cancer is expected to increase, with up to 15 million new cases and ..12 million deaths expected in the year 2020.Using cancer vaccines to harness the power of the cancer patients own immune system .is a highly attractive and innovative approach to cancer management.There are Autologus tumour vaccine: usingpatient derivedtumorcellsrepresentoneofthefirsttypesofcancervaccinestobetested..Allogenic tumour vaccine: containtwoorthreeestablishedhumantumorcelllines,

In1891,Dr.WilliamColeymadethefirstattemptto stimulatetheimmunesystemforimprovingacancerHe used IntratumoralinjectionsofinactivatedStreptococcuspyogenes..andSerratiamarcescens(Coley's Toxin)

79Tumour type Infectious agentCervical cancerHuman papilloma virusHead & neck cancerHuman papilloma virusHepatocellular carcinomaHepatitis B & C virusBurkitts lymphomaEpstein-Barr virusPost transplant lymphoproliferative diseaseEpstein-Barr virus

Nasopharyngeal carcinomaEpstein-Barr virusGastric cancerHelicobacter pyloriPrimary effusion lymphomaHuman herpes virus 8T- cell leukemiaHuman T-cell leukemia virus 1, 2Kaposis sarcomaKaposis sarcoma-associated herpes virus Infections associated with cancer developmentInfections associated with cancer development are

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-CSFAdverse 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.For Ca prostate PROVENGE Sipuleucel-TGot FDA approval on 29 April 2010..It is Autologous cellular immunotherapy.. It can be used in Treatment of asymptomatic or. minimally symptomatic metastatic castrate resistant ie hormone refractory prostate cancer.. 3 doses at 2-week intervals increased median survival by 4.1 months in phase 3 RCT .PROVENGE Each dose contains minimum of 50 million autologous CD54+cells. activated with GM-CSFAdverse events reported were chills, fatigue, fever, back pain, nausea, joint ache, and headache

81 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 cancerExpert Opin Investig Drugs. Jul 2009; 18(7): 1001-1011.doi:10.1517/13543780902997928

rV-PSA Prostvac is Recombinant vaccinia virus expressing PSA..Its Phase 3 PROSPECT trial is ongoing ..Which is Randomized, placebo-controlled, multi-centre, global 3-arm trial of PROSTVAC. in men with asymptomatic or minimally symptomatic, metastatic, castrate-resistant prostate cancer.

82Breast 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 inEarly-Stage Node-Positive Breast Cancer with Low to Intermediate HER2Expression withNeuVaxTreatment) 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;6:159-68HER2 is a most suitable target for BC vaccines and ..the most studied HER-2 derived peptide in clinical trials is E75.

It is 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 inEarly-Stage Node-Positive Breast Cancer with Low to Intermediate HER2Expression withNeuVaxTreatment is ongoing

It has 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) Melanoma: POL-103A vaccineContains 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 ongoinghttps://clinicaltrials.gov/ct2/show/NCT01546571 accessed on 15.1.15The presence of multiple antigens is an important element in maximizing the induction of tumor-protective immune responses.. and reducing a tumor cells ability to escape the immune response..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

Bladder cancer: CG0070 vaccineType of Oncolytic virus therapyStimulates cytokine GM-CSF to enhance anti-tumour immune responsePhase 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):2391-7Oncolytic virus therapy uses a modified virus that can cause destruction of tumour cells Cancer cells are destroyed by two different mechanisms: direct cell killing by the virus and immune-mediated cell killing stimulated by GM-CSFCG0070 vaccine is a

Type of Oncolytic virus therapyStimulates cytokine GM-CSF to enhance anti-tumour immune responsePhase 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.Ongoing phase III trialsCancer Vaccine & trialVaccine typeRenal cell cancerAGS-003(ADAPT trial)DC/APCs

GlioblastomaDCVax-LRindopepimut (ACT IV) DC/APCs

Peptides/proteinsEpithelial ovarian cancerCvac(CANVAS trail)DC/APCsPancreatic cancerGV1001(PRIMOVAX)Peptides/proteins

NSCLC

Stimuvax (START trial)

TG4010Peptides/proteins

Virus vectorsSCCHN

INGN 201

Virus vectors

SCCHN: squamous cell cancer of the head and neckNSCLC: non-small cell lung cancerLessons from cancer vaccine trials Cancervaccineshavedemonstratedminimaltoxicityin allclinicaltrialswith littleevidenceof autoimmunity Patientswhohavereceivedlesspriorchemotherapy aregenerallymore responsivetovaccinesTechnical and developmental challenges Challenges exist for developing combination therapy that incorporates cancer vaccine with established cancer therapeuticsWolchok 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.Cancervaccineshavedemonstratedminimaltoxicityin allclinicaltrialswith littleevidenceof autoimmunity Patientswhohavereceivedlesspriorchemotherapy aregenerallymore responsivetovaccinesTechnical and developmental challenges Challenges exist for developing combination therapy that incorporates cancer vaccine with established cancer therapeutics87Key factors driving vaccine market in India

Relatively low cost of manufacturingReasonable R & D expenditureLeading edge technology/Combination vaccinesAbundant skilled manpower Huge demandHigh potential for the new vaccines

Funding, slow regulatory approval and dependence on government persist as challenges for vaccine development in India

Funding is from Dept of Biotechnology, ICMR and Indian council of agricultural research

88From global perspective,

Rotavirus vaccinePneumococcol conjugateHPV vaccineFrom industrys perspective,

Focus is shifting towards DNA and recombinant vaccines

To conclude,From global perspective, the most important Indian vaccines in development are Rotavirus, Pneumococcol conjugate and HPV vaccines, which could offer low priced alternative to currently available vaccines from multinational firms. Also, an effective malaria vaccine would be a breakthrough, but history suggest that these candidates face long oddsThe resurgence of interest in vaccines is a part and parcel of this renewed focus on human immune system, which a still a frontier in many respects.

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