Vaccines in the Pipeline: - PowerPoint Presentation

1. Vaccines in the Pipeline:What’s New or Coming SoonSharon Rush, R.Ph.Clinical Assistant ProfessorUniversity of Texas College of Pharmacy

2. ObjectivesReview the effect of immunizations on morbidity and mortality rates of vaccine-preventable diseases in the United StatesReview how vaccines evoke an immune response and provide immunityDiscuss recently approved vaccines for general useDiscuss vaccines under FDA review or Phase III

3. Calvin and Hobbes is one of the best cartoon strips ever!Yes, it rocks!No, the kid is a brat!Calvin who?? Hobbes who??

4. MORBIDITY AND MORTALITY

5. Morbidity RatesDISEASE1950196019701980199020002011Diphtheria57969184353410Tetanus4863681489564359Pertussis120,71814,8094,2491,7304,5707,86715,216Polio (paralytic)33,3003,190339600Measles319,124441,70347,35113,50627,78686212MumpsNRNR104,9538,5765,292338370RubellaNRNR56,5523,9041,1251764Hepatitis ANRNR56,79729,08731,44113,3971,139Hepatitis BNRNR8,31019,01521,1028,0362,495VaricellaNRNRNR190,894173,09927,38212,041*www.cdc.gov/vaccines Morbidity and Mortality Report - May, 2011

6. Why are Pertussis cases increasing?People are no longer getting the pertussis vaccine Immunity from the pertussis vaccine wanes over timeI have no idea!

7. PertussisIn the June 2013 meeting, ACIP reported preliminary findings of recent studies involving the pertussis vaccine duration11 to 14 year olds:After 1st year  75% effectiveAfter 3rd year  56% effectiveOne to seven years post-vaccination41% effectiveness in 15 to 19 year oldsTen years post-vaccinationClose to pre-vaccination statusACIP working group does not recommend a second Tdap dose at this time despite increased burden of disease. New pregnancy guidelines will hopefully show improvement in cases.

8. Mortality Rates*www.cdc.gov/vaccines Morbidity and Mortality Report - May, 2011 DISEASE1950196019701980199020002011Diphtheria4106930110NATetanus3362317928115NAPertussis1,11811812111212NAPolio (paralytic)1,9042307200NAMeasles4683808911641NAMumpsNR4216212NARubellaNR1231180NAHepatitis ANRNRNA11276106NAHepatitis BNRNRNA294816886NAVaricellaNRNRNA7812044NA

9. Why was there a spike in measles cases in 1990?Vaccine shortageFailure to vaccinate children at the appropriate agePhilosophic or religious exemptions to vaccinations

10. IMMUNE RESPONSE

11. Let’s Follow the Flu….*Image from cdc.gov websiteTarget area for current influenza vaccines

12. Identification of these antigens are a key step in creating effective vaccines

13. Memory CellsOnce the infection is cleared, the body converts some of the lymphocytes into memory cells. If the infection occurs again, these cells can recognize the antigen quickly and respond.

14. LymphocytesT cells Cell-mediated responseDo not attack antigen directlyUse chemicals to eliminate infected cellsB cellsHumoral immune or antibody responseMake and secrete antibodies that grab onto the antigen like a puzzle. These antibodies bind to the microbe and render it unable to function

15. Antigen Load in VaccinesThe goal of most current vaccines is to stimulate the humoral immune or antibody response in B cells. Many infectious microbes can be defeated by antibodies alone.One antibody fits with one antigen, so millions of antibodies need to be present. Once vaccine is administered, the body recognizes it as an antigen and develops B and T cells particular to that antigen. Memory cells are produced for future infections.This cycle usually takes about 2 weeks to complete.

16. How many kinds of T cells are there in the immune response?OneTwoThreeMillions!

17. T Cells“Killer”Offensive T cellsProgrammed by prior exposure to the antigen“Sense” infected cells“Helper”Defensive T cellsSecrete chemical signals that direct the activity of other immune system cells. They activate “killer” T cells and B cells.Remember the role that these T cells play in the immune response. These T cells play a key role in new vaccine development.

18. RECENTLY APPROVED VACCINES

19. Which of the following influenza vaccines were available in 2013-2014?TrivalentQuadrivalentRecombinant egg-freeAll of the above

20. Influenza Vaccine 2013-2014Trivalent (IIV3)*An A/California/7/2009 (H1N1)An A/Victoria/361/2011 (H3N2)A B/Massachusetts/2/2012-like virusQuadrivalent (IIV4 or LAIV4)*Addition of a B/Brisbane/60/2008-like virus*Note new abbreviations

21. Influenza Vaccine 2013-2014VACCINE AND MANUFACTURERSPECIAL NOTESTYPEAfluria (CSL Biotherapies)IIV3Agriflu (Novartis)IIV3Fluarix Quadrivalent (GSK)IIV4FluLaval & FluLaval Quadrivalent (GSK)MDV – preservativesPre-filled syringes - PFIIV3 & IIV4Fluvirin (Novartis)IIV3Fluzone & Fluzone Quadrivalent (sanofi pasteur)QuadrivalentOnly one available for 6 months to 2 yrs of ageNo preservatives or latexPre-filled syringes or single dose vialsIIV3 & IIV4Fluzone High-Dose (sanofi pasteur)IIV3 onlyFluzone Intradermal (sanofi pasteur)IIV3 only*Note that all of these have differing age requirements – refer to package insert

22. Influenza Vaccine 2013-2014*No egg protein detectable in the final product due to multiple dilutions

23. The New Kids on the Block…Flucelvax®Cell-based Virus grown in liquid culture of animal cellsVaccine seed strain is passaged in eggs so could contain minute amount of albumin  egg allergy potentialPotentially affords a faster manufacturing response to a pandemicFlublok®Uses baculovirus-insect cell systemContains recombinant proteinOnly influenza vaccine considered 100% egg-freePotentially affords a faster manufacturing response to a pandemicShort shelf life of 16 weeks from production date

24. Influenza Vaccine 2014-2015A/California/7/2009 (H1N1) pdm09-like virusA/Texas/50/2012 (H3N2)-like virusB/Massachusetts/2/2012-like virusQuadrivalent vaccines will add:B/Brisbane/60/2008-like virus

25. H5N1Since December 2013 – 652 cases with 387 deaths confirmed in 16 countries. No evidence of sustained human-to-human transmission.¹January 8, 2014 – Public Health Agency of Canada reported first confirmed case of human infection with avian influenza A (H5N1)Person had traveled to Beijing, China Dec 27, 2013 and died January 3, 2014No reported cases in the United States¹World Health Organization. Recommended composition of influenza virus vaccines for use in the 2014-2015 northern hemisphere influenza season report. February 20, 2014.

26. H5N1 VaccineACIP reports there are two FDA-licensed H5N1 vaccines being stockpiled by the government for use in pandemicsACIP has been instructed to develop recommendations for:Use during non-pandemic periodUsed in certain high-risk groupsFindings to be reported at October 2014 meetingPossible vote at February 2015 meetingCDC website for detailed info on treatment and preventionhttp://www.cdc.gov/flu/avianflu/h7n9-faq.htm#vaccine

27. If a patient has anaphylaxis from eating eggs, can they receive the influenza vaccine?NoYesYes, with limitationsAre you kidding?

28. Egg Allergy and Influenza VaccineNew algorithm developedFurther differentiates reactionsIncludes new recombinant vaccine optionAddresses allergy testing procedures

29. NoNoYesYesYes

30. Egg Allergy and other VaccinesEgg allergy is specific to each vaccineHistory of egg allergy not relevant – use current guidelines algorithmInfluenzaVaricellaMMRHistory of egg allergy relevant – “Scratch test” recommended prior to administration via desensitizationYellow fever

31. Egg Allergy and other VaccinesPrevious reaction to vaccine:Identify symptomsAscertain risk of diseaseApplication of skin tests by physician with expertise in allergic conditions if applicableVaccination under control protocol based on results of skin test

32. Other Allergies and VaccinesNot considered a contraindication to administration of vaccines UNLESS allergy is deemed severe. Contact allergy is usually not considered a severe allergy.ThimerosolNeomycinLatex**FluMist has less flexibility due to its respiratory component. Wheezing IS a contraindication.

33. How many pneumococcal shots does a patient need in a lifetime after the recommended childhood series?1 or 23Every 5 yearsIt depends on the disease state

34. Pneumococcal VaccineNOTE: All information applies to patients after their recommended routine childhood vaccinations. People with no chronic illnesses get one dose ≥ 65 yrs of age People ≥2 y/o and up with chronic illness will get two to four doses depending on disease state

35. When do you Revaccinate?Revaccinate once (total of two doses in a lifetime) for:Healthy patients ≥65 y/o who received their initial dose before the age of 65 and ≥5 years agoPersons 19 through 64 years of age with the following conditions are revaccinated 5 years after the first dose and may receive a third dose depending on age of patient:Chronic renal failure or nephrotic syndromeFunctional or anatomic aspleniaImmunocompromised patients

36. Immunocompromised ConditionsCongenital or acquired immunodeficiencyHIV infectionChronic renal failureNephrotic syndromeLeukemiaLymphomaHodgkin diseaseGeneralized malignancyIatrogenic immunosuppression – diseases requiring treatment with immunosuppressive drugs, including long-term systemic corticosteroids and radiation therapySolid organ transplantMultiple myeloma

37. Three Doses of PPSV23Patients that are asplenic, immunocompromised or have chronic renal failure or nephrotic syndrome may receive up to three doses in a lifetime depending on time of diagnosis:Receive one dose of PPSV23 at time of diagnosisReceive second dose of PPSV23 five years laterReceive third dose of PPSV23 after the age of 65 if prior two doses were given before the age of 65NOTE: All doses need to be 5 years apart

38. PCV13Prevnar 13®Will replace PCV7 in childrenAdd one additional dose of PCV13 to current regimen of PPSV23Applies only to the following groups:Functional or anatomic aspleniaImmunocompromised patientsCSF (cerebrospinal fluid) leaksCochlear implantsDo NOT add additional dose of PPSV23 instead – Lack of evidence and possibility of waning response

39. PCV13 Additional Dose AdministrationIf patient is vaccine naïve: PCV13  PPSV23  PPSV23 + PPSV23≥ 8 weeks≥ 5 years65+ yrs of age

40. PCV13 Additional Dose AdministrationIf patient has received one dose of PPSV23: PPSV23  PCV13  PPSV23 + PPSV235 years between PPSV23 doses≥ 1 year≥ 8 weeks65+ yrs of age

41. PCV13 Additional Dose AdministrationIf patient has received two doses of PPSV23: PPSV23  PPSV23  PCV13 + PPSV23≥ 5 years≥ 1 year65+ yrs of age≥ 8 weeks

42. PCV13 Additional Dose AdministrationIf patient has received three doses of PPSV23: PPSV23  PPSV23 + PPSV23  PCV13≥ 5 years≥ 1 year65+ yrs of age

43. Meningococcal

44. Meningococcal and HIVMen who have sex with men (MSM)Small increased risk, burden of disease is lowHigh proportion of cases in HIV-infected patientsNo proposed recommendations at this time but will continue to studyHIV-infected patientsSurveillance data from 8-county area of Atlanta, GA from 1988-1993 revealed HIV-infected adults had almost 24-fold increased risk for developing meningococcal disease¹ACIP Meningococcal Work Group does not propose changes to current recommendations at this timeHIV cases declining + low incidence of meningococcal casesHIV-infected patients demonstrate short duration of protection with meningococcal vaccine²¹Stephens DS, Hajjeh RA, Baughman WS, Harvey RC, Wenger JD, Farley MM. Sporadic meningococcal disease in adults: results of a 5-year population-based study. Ann Intern Med. 1995: 123:937-40²ACIP October 23-24, 2013 minutes – Meningococcal Work Group

45. Meningococcal A StrainMeningitis Vaccine Project PATH, WHO and Bill & Melinda Gates FoundationSerogroup A predominates in Africa and AsiaMenAfriVac ® - monovalent, serogroup A conjugate vaccineImmunogenic in young childrenReduces carriage of bacteria in throat secretionsVery cost-effective due to monovalent vaccine - 40¢/dose Mass vaccination campaigns among 1 to 29 year oldsSuccessful clinical trials throughout India, Mali, Senegal and the Gambia*CDC website, World Health Organization website

46. Chad TrialOne of largest countries in AfricaMeningitis cases2009 – 30582010 – 5960 2011 – 3795Nationwide vaccination of 1 to 29 year olds from June through December 2012 with 81 to 95% vaccination rates Results – No Serogroup A cases during epidemic seasonMajority of cases due to Serogroup A

47. Adenovirus

48. AdenovirusViruses Common, many typesTypes 4 and 7 – severe outbreaks of respiratory illness among militaryCause of respiratory problems, headaches, eye infections, sore throatSpread easily through the airVaccine Used by military from 1971- 1999 but discontinued by manufacturerNew vaccine by Teva approved by FDA in March 2011 for respiratory ailments in 17 – 50 years of ageLive virus given as oral tablets – one with Type 4 and one with Type 7For military personnel only – not available to general publicContract with Department of Defense included performance criteria that the vaccine had to provide at least 80% protection of those persons immunized¹¹Towle AC, Azad A. How industry developed and manufactured Live Oral ADV4 and 7 Vaccine for a critical customer. Contract Pharma magazine website March 7, 2014

49. INVESTIGATIONAL VACCINES

50. What virus goes virtually undiagnosed in ~80% of patients?HIVNorovirusThe common coldHerpes Simplex

51. Herpes Simplex

52. HSV-2Herpes simplex virus type 2¹One of most common sexually transmitted infections worldwideOf those infected, >80% have not received a diagnosisStrong association between HSV-2 and HIV infectionsVaccinesGEN-003 by Genocea Biosciences, Inc.HSV529 by Sanofi Pasteur¹CDC Morbidity and Mortality Weekly Report. April 23, 2010/59(15): 456-459.

53. GEN-003Designed to treat HSV-2Administered with Matrix-M™ adjuvantNovel, saponin-derived product that demonstrates a balanced B and T cell immunostimulatory profileHarnesses power of T cell immunityIdentifies protective T cell antigens from naturally exposed humansCan potentially improve effectiveness of vaccine and reduce time needed to create vaccinesMarch 25, 2014 – Phase 1/2a study resultsDouble-blind, placebo-controlled, dose-escalation in 143 patients. Patients received three injections of assigned treatment at 21-day intervals and then followed for 1 year.Patients receiving 30mcg dose level experienced 72% reduction in lesion days six months after study initiation. Patients experienced 50% reduction in mean viral shedding that was maintained at six months.*Providence Journal website – www.providencejournal.com. Genocea Publishes Preclinical Data for Investigational Vaccine Candidate for HSV-2. March 18, 2013.*Monthly Prescribing Reference website – www.empr.com. Investigational Vaccine Efficacious in HSV-2 Trial. March 25, 2014.

54. HSV529Prevention of genital herpesPhase I trial sponsored by National Institute of Allergy and Infectious DiseasesWill test for safety and ability to generate an immune response in 60 adults aged 18 to 40 yearsCompletion expected in October 2016*The Medical News website – www.news-medical.net. Researchers launch clinical trial of investigational vaccine designed to prevent genital herpes disease. April 21, 2014

55. HPVV503 by Sanofi Pasteur9-valent HPV vaccineCurrent types 6, 11, 16 and 18Additional types 31, 33,45, 52 and 58Phase III study resultsStudy involved 16 to 26 year old non-infected females who received three doses over a 1-year period (N=7099)Prevented ~97% of cervical, vaginal and vulvar pre-cancersProtocol 002 study involved male subjects age 9 to 15 years and females age 9 to 26 years (N=3074)99.8 to 100% of adolescent males and females (age 9 to 15) seroconverted99.5 to 100% of females aged 16 to 26 years seroconvertedMerck Newsroom Home website – www.mercknewsroom.com. Merck’s Investigational 9-valent HPV Vaccine, V503, Prevented 97 Percent of Cervical, Vaginal and Vulvar Pre-cancers Caused by Five Additional HPV Types, in Phase III Study

56. HPV – 2 dose versus 3 doseGardasil® by Sanofi PasteurQuadrivalent vaccine currently dosed at 0,2 and 6 months)Randomized, Phase III, postlicensure, multicenter, age-stratified, noninferiority immunogenicity study Females aged 9 to 13 years (N=520)Females aged 16 to 26 years (N=310)ResultsGeometric Mean Titer ratios for 2-dose series noninferior to 3-dose series for all genotypes to 36 monthsAntibody responses for 2-dose series noninferior to 3-dose series for all genotypes at month 7Not for HPV-18 by month 23Not for HPV-6 by month 36More data on duration of 2-dose series protection needed before recommending reduced-dose scheduleDobson SRM et al. Immunogenicity of 2 Doses of HPV Vaccine in Younger Adolescents vs 3 Doses in Young Women. JAMA, May 1, 2013 – Vol 309, No. 17, 1793-1802.

57. HIVEarly studies targeted antibody responseHIV mutates rapidly and outer spike protein conceals itself from immune responseEvolving number of virus subtypes + recombinations VaccineALVAC® HIV (the prime) by Aventis Pasteur + AIDSVAX® B/E (the boost)

58. RV144 StudyThailand Ministry of Health and U.S. ArmyFour doses of prime ALVAC® HIV vaccine followed by two doses containing both vaccinesResults Infection rate 31.2% lower than the placebo groupEfficacy peaked early through initial 12 months and then declined quickly suggesting boosting doses would improve resultsModest effectiveness but has led to further research in HIV genome sequencesHIV Research website – www.hivresearch.org. U.S. Military HIV Research Program RV144 Trial

59. RV305 StudyBegan April 2012Evaluate boosting effect in current RV144 study patientsRV306 StudyBegan September 2013Using RV144 vaccine regimen to compare additional boosts Using 360 new volunteers for more immunogenicity dataPox-Protein Public-Private Partnership (P5)Begin 2016-17Improve and prolong the level of immunogenicityExtra vaccine boostImproved adjuvantsHIV Research website – www.hivresearch.org. U.S. Military HIV Research Program RV144 Trial

60. Scripps Research InstituteNew vulnerable site on HIV virus identified – PGT151Does not vary from strain to strainPGT151 is a protein used to infect cellsAntibody can attach to PGT151 and leave the virus incapable of infecting cellsBOTTOM LINE: Great strides are being made but no vaccine will be available until at least 2020.Science Daily website – www.sciencedaily.com. New point of attach on HIV for vaccine development. April 24, 2014

61. Norovirus

62. NorovirusLeading cause of severe gastrointestinal infection in the U.S.Causes ~90% of all epidemic non-bacterial outbreaks of gastroenteritis worldwideTransmitted via contaminated food or water , person-to-person contact or aerosolization of virusVaccineGI/GII by Takeda Pharmaceutical Company Limited

63. GI/GIIContains genotype GII.4 – most commonPhase ½ study resultsRandomized, double-blind, placebo-controlled, multi-center study with 98 healthy adults aged 18 to 50 years receiving two dosesWell tolerated Clinically relevant impact on incidence of disease after challengeIn those that experienced illness, severity was significantly reducedPositive trend in reducing viral shedding in stool observedTakeda website – www.takeda.com. Takeda Highlights Data from Clinical Trial of Investigational Norovirus Vaccine Candidate. October 4 and 7, 2013

64. Ebola

65. EbolaMainly seen in AfricaFatality rate up to 90%Transmitted via direct contact with bodily secretions from humans or other animalsNo specific treatment availableVaccineUT College of Pharmacy and two Canadian researchersOne-dose nasal vaccine proven effective in rodent and primate subjectsIssues with human trials

66. Meninigitis B

67. Meningitis BSerogroups B and C predominate in Europe, the Americas, Australia and New ZealandCurrent U.S. vaccines cover Serogroup CTarget outer polysaccharide capsule as the antigenMenB vaccine difficult to developOuter coating is not well-recognized by our immune system as an antigen  no immune response initiatedOuter membrane proteins vary greatly by strain, so vaccines have only been able to target specific strains

68. MenB Investigational VaccinesGenome sequence to MenB has been decodedFactor H-binding protein is present in over 1,800 menB isolates – LP2086Provides foundation for other new vaccines that need to protect against numerous and diverse strainsTwo vaccines undergoing clinical trialsPfizer – rLP2086Novartis - Bexsero® recombinant vaccine (rMenB)

69. rLP2086Persons 10 to 29 years of ageGranted Breakthrough Therapy designation March 20, 2014Phase 2 study published in Lancet Infectious DiseasesVaccine-induced bactericidal antibodies in healthy adolescents aged 11 – 18 years were broadly active against MenBAcceptable safety profilePhase 2 randomized, placebo-controlled, single-blind study of 2 and 3-dose schedules in healthy adolescents aged 11 – 18 years presented at 2013 Meningitis Research Foundation meetingOne month after last doseAfter 3 doses – 86-99% of subjects had functional antibodiesAfter 2 doses – 69 – 100% of subjects had functional antibodiesAdditional ongoing immunogenicity and safety studies since November 2012

70. Bexsero®Persons aged 2 months and olderRecently licensed in Canada, Australia and EuropeBreakthrough Therapy designation by FDA in April 2014Two-dose series1st dose at 0 months – protection for only a few months2nd dose at 1 to 6 months – long-term protection unknown, but robust responses seen after 2nd doseControlled use by FDA during outbreaksInterrupt disease spread  stopping outbreakUtilized in recent outbreaks at Princeton University (March-Nov 2013) and University of California-Santa Barbara (Nov 2013)Interim guidance to be presented at June 2014 ACIP meeting

71. Identify this picture: Meningococcal virusInfluenza virusPneumococcal virusMy cat’s favorite toy

72. Trends in influenza vaccineTarget the core that stays virtually the same for most common strains of the flu. This could offer immunity to emerging strainsVaccine will develop T cells, not B cellsResearch started in 2009http://inhabitat.com/scientists-unveil-blueprint-for-universal-flu-vaccine/

73. H7N9Avian influenza A (H7N9)Since February 2013 ¹355 human cases reported with 112 deathsAll in China except for one single case in Malaysia who traveled from ChinaVaccineCurrently nine candidate vaccine viruses available for researchSinovac Biotech has submitted a clinical trial application with the China Food and Drug Administration to commence human trials – Accepted January 29, 2014.²First global company to successfully develop and launch the H1N1 vaccine.¹World Health Organization website. Summary of status of development and availability of A(H7N9) candidate vaccine viruses and potency testing reagents. February 13, 2014.²Asian Scientist website (www.asianscientist.com). Sinovac Seeks Approval for H7N9 Vaccine Clinical Trials. February 11, 2014.

74. H9N2Avian influenza A (H9N2)Since December 2013Two cases reportedChina and China Hong Kong Special Administrative RegionMild illnesses belonging to A/chicken/Hong Kong/Y280/97 genetic lineageVaccineCurrently nine candidate vaccine viruses available for researchWorld Health Organization website. Summary of status of development and availability of A(H9N2) candidate vaccine viruses. February 20, 2014.

75. SummaryVaccines continue to be one of the major contributors to improved morbidity and mortality around the worldMost current vaccines are based on the antibody or B cell responseInvestigational and future vaccines are being based on T cell or genome sequencing that could provide quick responses to pandemics and multi-strain viruses/bacteria

76. QUESTIONS?Do not forget to turn in your clickers!