The Ring Leader

The Ring Leader

Affiliations andConflicts of Interest NC Academy of Family Physicians American Academy of Family Physicians: Commission on Health of the Public and Science; Chair, 2010. NC Immunization Advisory Council ACIP workgroups – Rotavirus, MMRV safety, Pertussis, Hepatitis,Zoster Past member, HPV young adult advisory panel, Merck. 2006-2009 No conflicts of interest

GoalsEvidence based RecommendationsNew Immunization IndicationsSafety IssuesState of Global ImmunizationsWhere Research is Headed

Vaccine Preventable DiseasesAnthrax Measles RubellaCholera Meningococcal Disease InfluenzaDiphtheria Mumps TetanusHepatitis A Pertussis TuberculosisHepatitis B Pneumococcal Disease Typhoid FeverHepatitis E Poliomyelitis Tick-borne EncephalitisHaemophilus InfluenzaeType BRabiesVaricella and HerpesZosterHuman Papillomavirus Rotavirus Gastroenteritis Yellow FeverJapanese Encephalitis

Vaccine Schedule Age 0 – 18 years (now combined) Adults age 19 and greater Catch-up schedule

Grading of Recommendations ACIP adopted GRADE process 10/28/2010 Stands for G - Grading of R - Recommendations A - Assessment D - Development and E - Evaluation Change made to make Evidence-Based decisions GRADE in use by WHO since 2008

Grading of Recommendations (cont.)Steps in GRADE Process:1. Formulate specific policy2. Identify and rank relative importance of outcomes3. Summarize relevant evidence for each outcome,including number needed to vaccinate to achieve outcomeif available4. Assess quality of evidence across outcomes

Grading of Recommendations (cont.)Steps in GRADE Process:5. Summarize quality of evidence across outcomes6. Review health economic data7. Assess balance of risks and benefits8. Determine recommendation category

Grading of Recommendations (cont.)Quality of Evidence HIGH – well done RCTs, very strong observational studies withlarge magnitude of effect MODERATE – RCTs, strong observational studies LOW – Limited RCTs, observational studies VERY LOW – limited observational studies, clinical consensus

Grading of Recommendations (cont.) Recommendation Categories: Category A Applies to ALL in AGE or RISK-Based population Category B Applies to SOME in a population Individual clinical decision making required Framework to consistently evaluate existing data Includes weighing of benefits and harms Cost effectiveness data

Grading of Recommendations (cont.) GRADE is not perfect Felt by some to not handle issues like herd immunity andpassive immunity very well It does require explicit judgment that is transparent

PERTUSSIS – What’s New(The Changing World of Tdap) Incidence increasing since 1980s 2012 – 42,000 reported cases Increase in both childhood and adolescent disease 2012 – 18 deaths, with 13 at < 3 Months 2006 – 10.8% Tdap Coverage, Age 13-17 2011 – 78% Tdap Coverage, Age 13-17 Infection despite vaccination

PERTUSSIS – What’s New(The Changing World of Tdap)

PERTUSSIS – What’s New(The Changing World of Tdap) 1940s – DTP – whole cell 1992 – DTaP for 4 th and 5 th doses 1997 - DTaP for entire 5 dose series Switch to acellular Pertussis (aP) has changedepidemiology of disease Studies show better persistence of protection in those with allor some whole cell vaccine

PERTUSSIS – What’s New(The Changing World of Tdap) Waning immunity 66-78% Vaccine Efficacy (VE) – in field observational studies Wanes in 3-4 years with acellular vaccine No demonstrable herd immunity Revaccination studies with Tdap Robust response with either 5 or 10 year booster No safety concerns identified

PERTUSSIS – What’s New(The Changing World of Tdap) Current recommendation – single dose of Tdap starting atage 11, except for pregnancy ACIP Pertussis Workgroup not recommending 2 nd Tdap dueto poor cost-benefit ratio from waning efficacy Health care workers – revaccinate? Cocooning – surround newborns with protected individuals

PERTUSSIS – What’s New(The Changing World of Tdap) Vaccinate those > 64 years – June 2012 Boostrix – FDA approved for age 10 and greater Adacel - FDA approved age 11 – 64. ACIP – can substitute Adacel if only product available (this is offlabel) No minimum interval time between Tdap and Td

PERTUSSIS – What’s New(The Changing World of Tdap)Tdap in Pregnancy October 2011- ACIP Recommendation to give in pregnancy, late2 nd /3 rd trimester. October 2012 – ACIP recommendation to give with EACHpregnancy, late 2 nd /3rd trimester. Ideal – 27 – 36 weeks.Why? Antibody levels wane between pregnancies within 1-2 years. Safety concerns – data is minimal but no identified concerns. Thru 2012, only 2.6% of pregnancies received Tdap (survey).

PERTUSSIS – What’s New(The Changing World of Tdap) Emergence of vaccine-resistant Bordetella Pertussis First seen in Philadelphia in 2012 Reported in France, Japan, Finland Strains do not produce pertactin Importance remains uncertain

Meningococcal Disease –What’s New Two dose series – at 11-12 years with booster at 16 years Multiple Vaccines available Polysaccharide Quadrivalent Vaccine. MPSV4 –Covers A,C,Y,and W. Single dose, age 2 and up. Since 1981. Menomune. Conjugate Quadrivalent Vaccines. MenACWY MenACWY-D. 2005. Menactra MenACWY-CRM. 2010. Menveo Conjugate Bivalent Vaccine. MenCY Hib-MenCY-TT. 2012. MenHibrix. Contains Hib and small amountof tetanus toxoid

Meningococcal Disease –What’s New Vaccinate High Risk Infants – Age 2 months – 23months. Serogroups C and Y. High Risk groups Persistent complement pathway deficiencies Anatomic or functional asplenia, including sickle cell disease ACIP recommendation, October 2012 – 4 doses of HibMenCY at2, 4, 6, and 12-15 months If used, use HibMenCY for all 4 Hib doses No recommendation for routine immunization

Meningococcal Disease –What’s New Vaccination of High Risk 9-23 month olds Current recommendation also includes use of 2 doses ofMenACWY-D (Menactra), minimum 8 weeks apart.(MenACWY-CRM does not have this indication.) Use either HibMenCY or MenACWY-D for any given child.Don’t mix. No product preference, per ACIP

Meningococcal Disease –What’s New Meningococcal A - MenAfriVac. First vaccine to be able to travel outside cold chain Up to 40 degrees C for up to 4 days Not available in USA Meningococcal B First time vaccines available for B strains 2 Vaccines licensed in Europe, 2013 4CMenB - Bexsero (Novartis) Bivalent recombinant lipoprotein 2086. In US studies inadolescents, including at Duke. (Pfizer)

Pneumococcal Disease –What’s New Success of PCV7 in Preventing PneumoniaAdmissions PCV7 introduced in 2000 Studied Pneumonia Admission rates through 2009 Age < 2 – 47,000 Fewer admissions annually.Reduction has been sustained over a decade. Age 85 + - 73,000 Fewer admissions annually All age groups – 168,000 Fewer admissions annually Griffin, et al. NEJM 2013; 369:155-163.

Pneumococcal Disease –What’s New PCV 13 Give routinely to immunocompromised PCV 13 – naïvechildren age 6-18 years This includes: Asplenia Cochlear implants HIV CSF leaks Other immunocompromising conditions Before, it was a permissive indication FDA approval is for 6-17 years

Pneumococcal Disease –What’s New PCV 13 in Immunocompromised Adults Age 19 and older Conditions – Asplenia, Chronic renal failure, CSF leaks, cochlearimplants Single PCV 13 dose followed by PPSV23 at least 8 weeks later PCV 13 to be given at least 1 year after PPSV23 if history of priorPPSV23 FDA – licensed for adults age 50 and up ACIP – limited to recommendation currently as above

Pneumococcal Disease –What’s New Should PCV 13 be used in healthy adults, age 50-64? Estimated 20-50,000 people die of pneumococcaldisease each year PCV 13 impacts T Cell immunity Getting PPSV 23 blunts immune response to PCV 13 Cost effective? JAMA article says yes Smith, et al. JAMA. 2012;307(8):804-812.

Shingles Single dose, age 60 and up – ACIP recommendation FDA - licensed for age 50 and up Can give 2 years after episode of Shingles – consensusopinion Efficacy of vaccine diminishes with increasing age atvaccination Need for booster dose? Being studied. Covered by Medicare Part D – complicates giving of vaccinein medical offices.

Hepatitis B –What’s New Now recommended for persons with Diabetes Recommendation - October 2011 Age < 60 years – as soon as possible after diagnosis Age 60 and up – at discretion of treating clinician Issue raised due to outbreaks in assisted living facilities Decreased vaccine efficacy with increasing age atvaccination

Hepatitis B –What’s New Healthcare personnel (HCP) issues CDC recommendations re immunizations in HCP - Acute hepatitis B does occur in HCP, either in unvaccinated ornon-responders. What to do with HCP vaccinated in first year of life? How to handle exposures? CDC is preparing guidance statement

Hepatitis A ACIP Recommendation – May 2006 Two dose series, starting at 12 months Booster after 6 month interval minimum Important travel vaccine (as well as Hep B) Recommended for unvaccinated persons anticipatingclose contact with international adoptees from endemiccountries during first 60 days of adoptee’s arrival

HPV –What’s New Quadrivalent vaccine (HPV4) - licensed June 2006 Bivalent vaccine (HPV2) - licensed October 2009 Known to prevent Precancerous lesions of the cervix Genital warts - HPV4 only Precancerous lesions of the anus in men (HPV4 only) –added December 2010 Safety 40 million doses HPV4 through September 2011 Similar adverse effects to prelicensure studies

HPV –What’s New Two Vaccines available – HPV2 and HPV4. Both are 3 doseseries HPV4 - male and female HPV2 - female HPV in males – 3 dose series at age 11-12 Catch up for males, age 13-21. May vaccinate in males, age22-26 Up to age 26 for immunocompromised and MSM populations

HPV –What’s New HPV in Oral Cancer Strains 16 and 18 Peaks at 30-34 years and 60-64 years Male > Female No prevention data yet Costa Rica Vaccine Trial re: Oral Cancer Conducted in young women 92 % VE against HPV 16 100 % VE against HPV 18 ( but very small numbers)

Influenza –What’s New Vaccine formulations for 2013-14 Flu season -11 different formulations/manufacturers Inactivated Influenza Vaccine, Trivalent, standard dose (IIV3) Inactivated Influenza vaccine, Trivalent, high dose (IIV3) - Age65 and greater. (Fluzone High-Dose, Sanofi). Inactivated Influenza Vaccine, standard dose, Trivalent (IIV3),intradermal. Age 18-64. (Fluzone Intradermal, Sanofi).

Influenza –What’s New Inactivated Influenza Vaccine, Quadrivalent (IIV4), standarddose 6 months and up – Fluzone (Sanofi). Approved 6/7/13 3 years and up – Fluarix (GSK). Recombinant Influenza Vaccine Trivalent, (RIV3). Age 18 – 49.(FluBlok, Protein Sciences). 100% Egg Free. Live-attenuated Influenza Vaccine, Quadrivalent, (LAIV4).Intranasal. Age 2 - 49. (FluMist, MedImmune)

Influenza –What’s NewEgg Allergy Can use recombinant influenza vaccine (RIV) Cell Culture IIV3 (ccIIV3) vaccine has very small amount ofegg in it FluCelVax, Novartis. Can use in office if mild allergy (hives only) and provide 30 minutesof monitoring

Influenza –What’s New Trivalent Vaccine Composition - 2013-14 A/(H1N1)/California/7/2009 – like virus A/ (H3N2)/Victoria/361/2011 – like virus (new) B/ Massachusetts/2/2012 – like virus (new) Quadrivalent Vaccine Composition - 2013-14 The above three PLUS B/Brisbane/60/2008 – like virus

Influenza –What’s New Vaccine Effectiveness Midseason, 2012-2013 season Influenza A 6 Months – 17 years - 64% 18 – 49 years - 52% 50 - 64 years - 63% 65 + Years - 27% Influenza B 64 - 75% Not enough numbers to break out by age

Influenza –What’s New Issue of possible waning immunity 2 Recent European case-control studies Both are small Both looked at 2011-12 Season UK study (Pebody) Looked at H3N2 VE – 53% for < 3 months post vaccination VE - 12% for > 3 months post vaccination Numbers too small to see any difference in age 65+

Influenza –What’s New Spain study (Castilla et al) 61% VE - 0 – 100 days Post Vaccination 42% VE - 110-119 days Post Vaccination 35 % VE - >119 days Post Vaccination Needs further review and research Brings up issue of timing of vaccination Ideal time to vaccinate for any given season is unknown At this time, no change in recommendations

HIB –What’s New Updated Recommendation Statement - 2013 Attention to special populations Elective splenectomy – 1 dose prior if unimmunized Asplenic - >59 months & adults – 1 dose if unimmunized HIV - >59 months – 18 years - 1 dose if unimmunized HIV – Adults - Not recommended Hematopoietic Stem cell transplant recipients 3 doses, at least 1 month apart, starting 6-12 months aftertransplant

HIB –What’s New HibMenCY is a valid HIB vaccine Should be used in context of meningitisrecommendations Recommended that entire HIB series be completed withHibMenCY once HibMenCY is started

MMR –What’s New Third dose of MMR has been used at several locationsfor outbreaks of mumps Data currently insufficient either for or against 3 rd MMR dose inmumps outbreaks CDC Guidance - May administer to specifically identified targetpopulations Recommended for children age 6-11 months travelingoutside of US (including to Europe) – does not count aspart of two dose series

Rotavirus –What’s New 2 Vaccines Pentavalent – live attenuated, bovine-human Monovalent – live attenuated, human Vaccine effectiveness – 70-84% New Intussusception Data Estimated risk 1/20,000 – 1/100,000 in first 6 days Benefit felt to far outweigh risk Waning studies Pentavalent – no waning after 4 years Monovalent – no waning after 2 years ( limited numbers so far)

Adenovirus –What’s NewVaccine for Adenovirus, Types 4 and 7 Vaccine available from 1971 – 1999 Use ended due to production stopped Approved in October 2011, same vaccine, new manufacturer Only used in military recruits by Department of Defense In first 18 months, felt to prevent 15,000 cases with 250,000vaccinated

Japanese Encephalitis –What’s New Mosquito borne flavivirus – similar to Dengue Leading cause of encephalitis in Asia

General Recommendations –What’s New Febrile seizures with giving IIV3 and PCV13 together One additional febrile seizure per 2,200 children ACIP feels benefits outweighs risk Live vaccine rule trumps 4 day grace period Live vaccines must be given at least 28 days apart

Vaccine Safety Institute of Medicine (IOM) Report Found the childhood schedule through age 6 to be safe Focused on overall safety, not individual vaccines. Recommended vaccine safety be systematically assessed

Vaccine Safety VAERS – Vaccine Adverse Event Reporting System Frontline spontaneous reporting system Open to anyone to report VSD – Vaccine Safety Datalink Collaborative effort with CDC and 9 managed care entities Encompasses 9.8 million people

Vaccine Safety CISA – Clinical Immunization Safety Project CDC and 7 academic centers Includes one at Duke, led by Dr Chip Walter Expert collaboration Vaccine safety assessments and clinical research Post Licensure Rapid Immunization SafetyMonitoring System ( PRISM) FDA – new surveillance system

Vaccine Safety Influenza Safety Reports, thru June 2012 Fluzone and Febrile Seizures VAERS – increase in 12-23 months, 2010-11 and 2011-12 VSD – increase in 6-23 months, 2010-11, 2011-12 High dose – 2 nd season, 600 VAERS reports, 88% nonserious Intradermal – 51 VAERS reports, 96 % non-serious

Vaccine Safety H1N1 and Guillain-Barre Syndrome – 2009 H1N1 – meta-analysis of 6 reporting sites showed 1.6excess cases per million doses. Total of 23 million dosesreviewed. Salmon et al. Lancet, 2013; 381(1461-68). 2009 H1N1 – Quebec study showed 2 excess cases per milliondoses. Decuninck, et al. JAMA, 2012: 308 (2): 175. VAERS – no disproportionate GBS after TIV/LAIV, 2011-12 VSD – no increase in GBS, 2011-12

Vaccine Safety No link between number of immunizations given on any singleday and autism spectrum disorder (ASD) No link between total number of immunizations received byage 2 and ASD Stefano, et al. Journal of Pediatrics, April 2013.

Vaccine Safety Tdap in Pregnancy VAERS - 132 reports from 2005-2010 Most unaware of pregnancy at time of vaccination 2 Fetal deaths 2 preterm births 1 Major Birth Defect No unusual or unexpected outcomes VSD 3 phase study ongoing Completion of studies at end of 2015

Global Actions Global Alliance for Vaccines and Immunizations (GAVI) World Health Organization - Since 1999, from Bill and Melinda Gates Foundation 74% decrease in measles deaths from 2000 to 2010 Still, 430 Children die daily from measles 100,000 Children born annually with congenital rubella – littlechange from 1996. Focus on increasing access to Rubella, PCV 13, Rotavirus, HPV

Global Actions Global Polio Eradication Initiative 1988 – 1,000 kids getting polio daily 2012 – 223 cases worldwide – is 1/3 of 2011 total. Strategic Plan, 2013 – 2018 Present still in Nigeria, Pakistan, Afghanistan Complicated by killing polio vaccine workers Calls for last wild polio by late 2014. Certification of eradication by late 2017 6 year $ 5.5 billion budget – 1/3 thru Gates Foundation.Rotary International also major contributor.

Vaccine Development Dengue Mosquito borne flavivirus No licensed vaccine In Phase II/III trials, Sanofi Pasteur Safe but no clinically significant efficacy West Nile Mosquito borne flavivirus 5,674 cases reported in 2012. Most since 2003 286 deaths in 2012 in USA – most ever Vaccine in Phase II trials. Available for horses

Vaccine Development Hepatitis E – identified in 1983 Fecal-oral transmission 70,000 deaths annually world wide May cause up to 10% of pregnancy related deaths in lowincome/underdeveloped nations GSK – Phase II in early 2000’s, not pursued Vaccine approved in China in 2012

Vaccine Development Staph Aureus – In Phase I trials. Appears safe. 2 different vaccines in development Tuberculosis BCG remains in use, created in 1921, unreliable Several in the works; Phase IIb best so far Clostridia Dificile Work ongoing for over 2 decades Against both Toxin A and Toxin B Trials include both injectable and mucosal vaccines

Vaccine Development HIV Complex due to variability of virus, especially its proteinenvelope Likely will need to both cell-mediated and antibody-basedresponses for vaccine to be successful About 30 trials in progress, in Phase I or Phase II Getting closer but a long ways to go

Vaccine Development Hepatitis C 170 million chronically infected world-wide 3-4 million new cases world-wide Single stranded RNA virus High genetic variability with 6 genotypes and over 100 subtypes Very early in process Just finished Phase I of Phase I/II trial – waiting to hear if canproceed

Vaccine Development Group B Strep Important cause of neonatal morbidity/mortality Septicemia, pneumonia, meningitis Early-onset disease – In 1 st Week Late-onset disease - From 1 st Week- 3 Months Multiple serotypes of bacterium Ongoing work for 20 years Likely will be multivalent conjugate vaccine Recent Phase I/II trial (Novartis) with trivalent vaccine

Vaccine Development Malaria Trials ongoing for past 15-20 years Evolutionary change, rapid reproduction, and emergenceof drug resistance No effective vaccine yet Needs both cell-mediated and antibody-based responses GSK has vaccine in Phase III trials

Final Thoughts “ All scientific work is incomplete – whether it beobservational or experimental. All scientific work is liable tobe upset or modified by advancing knowledge. That does notconfer upon us a freedom to ignore the knowledge wealready have, or to postpone the action it appears to demandat a given time. Who knows, asked Robert Browning, but theworld may end tonight? True, but on available evidence,most of us make ready to commute on the 8:30 the nextday.”- Sir Austin Bradford Hill, English Epidemiologist


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