for Adults and Adolescents: An Update Nothing to disclose….

Lisa G. Winston, MD Professor of Medicine, University of California, San Francisco Vice Chief, Inpatient Medical Services and Hospital Epidemiologist Zuckerberg San Francisco General

Diseases/Pathogens with Diseases/Pathogens with Generally Available in the U.S. Vaccines for Special

Tetanus Hepatitis A Populations Haemophilus influenzae type B Plague Pertussis Human papillomavirus Measles Polio Tularemia Mumps Influenza Smallpox Rubella Rabies Anthrax Varicella Typhoid Adenovirus Meningococcus Yellow fever Pneumococcus Japanese encephalitis Tuberculosis - BCG Hepatitis B Rotavirus

1 Key Resource

Centers for Disease Control and Prevention http://www.cdc.gov/vaccines/ http://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/index.html

February 4, 2016 - http://www.cdc.gov/vaccines/sc hedules/downloads /adult/adult-combined-s chedule.pdf

Vaccines to be Covered Measles outbreaks Hepatitis B – updated indication

Pneumococcal Measles outbreak Disneyland Meningococcal started late December 2014, ended April 2015 Pertussis (Tdap) • At least 146 cases with link • 7 states, Mexico, Canada Influenza • More than half in adults Varicella (Zostavax) 2014: Human Papillomavirus • Record year – 668 cases in 27 states • Large outbreak in unvaccinated Amish communities in Ohio • Many cases linked to importation from Philippines

2 California Law Antivaccination sentiment Signed 6/30/15; takes effect 7/1/16 What techniques are most persuasive? All children in public school, private school, or daycare must be vaccinated against Carefully designed study administered pre and post education surveys to 315 participants n Measles, mumps, rubella, pertussis, diphtheria, tetanus, Haemophilus influenzae type B, polio, Randomly assigned to education on dangers of hepatitis B, varicella measles vs. dispelling autism myths vs. control Medical exemptions permitted Attitude change score was positive (pro vaccine) No personal belief exemptions after disease risk education; autism correction No religious exemptions and control groups had no change

n n CA joins Mississippi and West Virginia as the only Greatest change with most negative vaccine attitudes states without personal belief and religious before disease risk education exemptions Proc Natl Acad Sci USA 2015;112:10323

Hepatitis B Vaccine Pneumococcal Vaccines

Vaccinate previously unvaccinated adults Two vaccines now used routinely in adults 65 ages 19 – 59 with diabetes as soon as and older possible after diagnosis Pneumococcal polysaccharide vaccine n Risk for acute hepatitis B estimated 2x higher n PPSV-23 (Pneumovax); 23 valent than general population n In use since 1983 n Increased risk presumed related to blood n Efficacy against pneumonia in older adults is unclear glucose monitoring or other procedures Pneumococcal protein involving instruments n PCV-13 (Prevnar); 13 valent n Persons with diabetes who are 60 and older n Recommended for selected adults in U.S. in 2012 may be vaccinated n Additionally recommended for 65 and older in 2014 MMWR. December 23, 2011 / 60(50):1709-11 n In adults, only one-time dose indicated

3 Pneumococcal 13-Valent Single dose PPSV-23 (< age 65) Conjugate Vaccine for Adults Condition PCV-13 PPSV-23 PPSV-23 single dose single dose revaccinate 5 in the Netherlands: 84,496 adults > 65 years after 1st randomized to PCV13 vs. placebo – (CAPiTA trial) dose Heart disease X n 46% fewer first cases of vaccine type pneumococcal community acquired pneumonia (CAP) Lung disease – X – primary outcome including asthma Diabetes mellitus X n 75% fewer first cases vaccine type invasive pneumococcal disease Alcoholism X Cirrhosis X n No difference CAP from any cause Cigarette smoking X Long-term care X resident Native populations X New Engl J Med 2015; 372:1114-25 with high risk

Single dose PCV-13 and repeat PPSV-23 five years after first dose Single dose PCV-13 and single (< age 65) Condition PCV-13 PPSV-23 PPSV-23 single dose single dose revaccinate 5 dose PPSV-23 (< age 65) years after 1st dose Sickle cell disease X X X Condition PCV-13 PPSV-23 PPSV-23 Asplenia X X X single dose single dose revaccinate 5 HIV X X X years after 1st Renal failure X X X dose Nephrotic syndrome X X X CSF leak X X Leukemia X X X Cochlear implant X X Lymphoma X X X Multiple myeloma X X X Hodgkin disease X X X Generalized malignancy X X X Solid organ transplant X X X Other X X X or

4 Sequencing pneumococcal Meningococcal Vaccines - vaccines in adults MenACWY If PCV-13 and PPSV-23 both indicated, give PCV- Two tetravalent protein conjugate 13 first vaccines (Menactra, Menveo) covering

n New recommendation for 65 and older: wait at strains A, C, Y, W-135

least one year before administering PPSV-23 n Menactra: 9 months – 55 years; Menveo –

n Wait at least 8 weeks for less than age 65 2 months – 55 years If PCV-13 and PPSV-23 both indicated and PPSV- n Advantages compared to polysaccharide 23 has already been administered vaccine Longer lasting antibody titers n Wait at least one year before PCV-13 (no change) Good antibody response to revaccination

n Serogroup B not covered by tetravalent vaccines (B, C, and Y circulate in U.S.)

MenACWY vaccine – Who should get MenACWY vaccines? summary table

Risk group Primary series Age 11-18 1 dose, preferred age 11 •Age 16, if primary dose or 12 age 11 or 12 Recommended as routine for ages 11 - 18 – ideally •Age 16-18, if primary given at age 11-12 visit dose age 13-15 *Also, 1st yr. college •No booster if primary “Catch up” at high school or college entry if not students in residence dose on or after age 16 halls up to age 21 given at age 11-12 Age 2-55 with 2 doses, 2 months apart Every 5 years n Increased risk for college freshmen in dormitories complement deficiency or functional or anatomic Second doses now routine for adolescent and asplenia teenage vaccinees Age 2 – 55 with 1 dose Age 2-6: after 3 years prolonged increased risk Age 7 and older: after 5 of exposure years

MMWR. January 28, 2011;60:72-76

5 Who else should get MenACWY vaccine? meningococcal disease United States Given to military recruits, travelers/residents with geographic risk, microbiologists Incidence of all serogroups has declined

Other notes: n Decline occurred prior to routine MenACWY n Meningococcal polysaccharide vaccine is used for those 56 vaccine years and older if vaccine is indicated n In 2013: 564 culture and PCR confirmed n required for pilgrims going to Hajj or Umrah in cases Saudi Arabia n n Clusters in New York City and Los Angeles among men Historically, only 2-3% of US cases occur in who have sex with men – vaccine may be recommended outbreaks, i.e. most cases are sporadic before travel n Serogroup B now causes about 40% of cases in adolescents and young adults

Recent serogroup B outbreaks Two meningococcal serogroup B vaccines available in US linked to college campuses Both approved ages 10-25 years Princeton 2013-2014: 9 cases (1 death) MenB-FHbp (Trumenba) approved Oct 2014 n 3-dose series

UC Santa Barbara 2013: 4 cases (no deaths) n Contains two recombinant factor H binding protein University of Oregon 2015: 7 cases (1 death) antigens One from each subfamily A and B Santa Clara University 2016: 3 cases (no MenB-4C (Bexsero) approved Jan 2015 deaths) n 2-dose series

n Contains four components Cover most but not all serogroup B strains Local and systemic reactions common

n More common than with other adolescent vaccines

6 Recommendations for MenB vaccines Recommended for persons 10 years and older at elevated risk due to n Persistent complement component deficiencies Vaccine combinations: Including taking drug eculizumab n Childhood DTaP: diphtheria , n Anatomic or functional asplenia tetanus toxoid, and acellular pertussis

n Routine exposure (microbiologists) n Adult/adolescent Td and Tdap: tetanus n Serogroup B outbreak toxoid and reduced dose diphtheria toxoid MMWR 2015. 64(22);608-612 +/- reduced dose acellular pertussis antigens Additional category B recommendation (individual decision making) ACIP vote June 2015: MenB vaccine may be given to adolescents and young adults ages 16-23 to provide short-term protection; preferred age range 16-18

Acellular pertussis vaccine in adults Pertussis Vaccine and adolescents – how well does it work? Pertussis wanes over time 2781 subjects 15 – 65 yrs received reduced Peaks every 2-5 years in U.S., including dose acellular pertussis vaccine or hepatitis A n 2005, 2010, 2012, 2014 placebo Followed for 2.5 yrs Based on primary pertussis definition, vaccine 92% effective

Ward et al, NEJM, Oct. 2005

7 Waning immunity after acellular vaccination Why is acellular vaccine less California outbreak 2010: protective? n Most pediatric cases were vaccinated as recommended Fewer antigens n High levels of disease in pre-adolescents, especially 10- n Acellular vaccines – up to 5 antigens

year-olds J Pediatr 2012;161:1091-6 n Whole cell vaccines - ~ 3000 antigens

Kaiser Permanente study in CA kids: odds of n Priming more robust with whole cell

pertussis increased by 42% per year in the 5 years after n Different type of T cell response completing DTaP New Engl J Med 2012;367:1012-19 Antigen balance Kaiser Permanente study: n High levels of antibody to pertussis toxin may have n 263,496 persons 8-20 years old who received acellular blocking effect on antibodies to other antigens vs. whole-cell vaccine (at least one dose) Genetic changes in Bordetella pertussis n ~ 8.6 relative risk of pertussis for 5 doses acellular vaccine Clin Infect Dis 2013;56:1248-54 n Especially pertactin deficiency

Tdap – Recommendations

For adolescents, give Tdap instead of Td at routine 11-12 yr visit Pertussis rates began increasing in 1980s For adults 19 and older, give single dose Tdap to replace a dose of Td n Well before acellular vaccines Rate today estimated 20-fold less than pre- Can be given at any interval from last tetanus- vaccine era and reported rates influenced by containing vaccine

n More testing Strongly recommended for adults who will have

n More sensitive tests – PCR contact with infant < 12 months

n False positives, e.g. due to other Bordetella species Recommended for every pregnancy at 27 – 36 When acellular vaccine fails in children, illness weeks (new in 2012) less severe than in unvaccinated MMWR 2011 / 60(41):1424-26

8 Pertussis – Recommendations Other vaccination opportunities/priorities: Indicated for all people older than 6 months vSubstitute single dose Tdap for Td in wound n Unless there is a contraindication management or if primary series unknown or Egg – risk assessment incomplete Severe previous reaction vGive immediately post-partum if not given Guillain-Barre – relative contraindication previously v“Cocooning” – vaccinate parents, siblings, grandparents, etc. who anticipate contact with infant < 12 months vAll healthcare workers with patient contact should receive Tdap

2016-17 Influenza Vaccine Influenza Season Summary

2015-16: relatively mild A/California/7/2009 (H1N1)-like (same) n Preliminary estimated vaccine effectiveness 59% A/Hong Kong/4801/2014 (H3N2)-like (new) B/Brisbane/60/2008-like (Victoria lineage – Contrast to 2014-15: moderately severe previously in quadrivalent only) n Rate of hospitalization for age 65+ highest since For quadrivalent vaccine add: surveillance began 2005-6 B/Phuket/3073/2013-like (Yamagata lineage - n Overall vaccine efficacy against any influenza same) estimated 19%

9 Inactivated standard dose High dose vaccines given IM Trivalent Quadrivalent: 2 influenza A strains, 2 influenza B Licensed for ages 65 and older strains 60 µg hemagglutinin per strain compared with • 3 brands available in U.S. for adults 15 µg in regular dose Trivalent: 2 influenza A strains, 1 influenza B Enhanced immune response in those 65 and older and other populations, including people living with strain HIV • 3 brands available in U.S. for adults Local reactions (mild to moderate) more common J Infect Dis 2009;200:161-3

High dose inactivated vaccine Live Attenuated Influenza Vaccine (LAIV) Studies with clinical outcomes:

n 2-year study with 31,989 participants randomized to Trade name FluMist high dose vs. standard dose: 1.4% vs. 1.9% with Quadrivalent confirmed influenza (relative efficacy 24.2%) New Engl J Med 2014;371:635- 45 Heat sensitive and cold adapted n Retrospective study at VA 2010-2011; 25,714 Approved for healthy persons ages 2 – 49 veterans high dose, 139,511 standard dose. No difference in hospitalization for influenza or n More contraindications than inactivated vaccine pneumonia, except in those 85 and older Runny/stuffy nose most common side effect Clin Infect Dis 2015;61:171-6 n Cluster randomized trial in 823 nursing homes, 53,000 residents. All-cause hospitalization decreased from 20.9% to 19.7% with high dose vaccine. NNT=81. Statistically significant. ? Clinically significant. IDWeek 2015, late breaker oral abstract session

10 Additional influenza vaccines LAIV efficacy licensed in U.S. In adults, studies suggest LAIV has equal or less Recominant vaccine using baculovirus expression efficacy than inactivated vaccine system (FluBlok) In children, some studies have shown greater n No exposure to eggs; trivalent; ages 18+ efficacy for ages 2 – 8; more recent studies have Cell culture derived vaccine using canine kidney shown comparable (or even less) efficacy cells (Flucelvax) In 2014-15, CDC preferentially recommended n Trivalent; ages 18+ LAIV for healthy children ages 2 – 8 years if no One vaccine can be administered by jet injector contraindications and vaccine immediately (Afluria) available n Trivalent; ages 18-64 Return to no preference for 2015-16 Intradermal vaccine (Fluzone intradermal)

n Quadrivalent; ages 18-64; needle one-tenth standard length; more local reactions

Varicella Vaccine (Varivax) – Zoster Recommended for all adults without (Zostavax) immunity (history of varicella or laboratory evidence) Oxman et al, NEJM, June 2005 Avoid in pregnancy and with most Randomized trial 38,546 adults > age 60 immunocompromise n Excluded if history of zoster, immunocompromise Given as 2 dose series for all ages Potency much greater (at least 14x) than vaccine to prevent primary varicella n Two doses 98% effective in children Shapiro et al, Journal Infect Dis 2011;203:312-15 Zoster incidence reduced by > 50%; post herpetic neuralgia reduced by > 65% Average annual mortality has declined Injection site reactions common 88% overall and 96% under age 50 Marin et al, Pediatrics 2011;128:214-20

11 Varicella Vaccine – Zoster Varicella Vaccine – Zoster (Zostavax) (Zostavax)

Recommended a single dose of zoster Main questions concern cost effectiveness – vaccine for adults age 60 and above, even if multiple studies prior history of zoster n Vaccine cost ~ $150 per dose n Societal costs $27,000 – 112, 000 per QALY Contraindicated in many, but not all, immunocompromised persons (e.g. okay in Follow up subjects in Shingles Prevention Study HIV if clinically well and CD4 count > 200) n Efficacy for zoster prevention estimated to last 8 years Clin Infect Dis 2015;60(6):900-9

Human Papillomavirus (HPV) Vaccines

Genital HPV most common sexually transmitted in the U.S. Quadrivalent HPV vaccine () NEJM 2015;372:2087-96 n Contains major capsid protein L1 from types 6, 11, 16, 18

• Phase 3 study; 7698 received vaccine, 7713 placebo Bivalent HPV vaccine () protects against • Adults 50 and older stratified by age types 16 and 18 • Two dose series n Only licensed in females • 6 cases zoster in vaccine group, 210 in placebo group Types 16 & 18 associated with 66% cervical cancer • Mean follow up 3.2 years • 97% efficacy Types 6 & 11 associated with 90% genital warts • No difference in efficacy by age

12 Nine-valent HPV vaccine HPV Vaccines Recommendations for Use Routine vaccination beginning at age 11-12 FDA approved December 10, 2014 n Okay to start as young as age 9

n Phase 3 trial of 9-valent vaccine (Gardasil 9) Females: vaccinate through age 26 against 6, 11, 16, 18 plus 31, 33, 45, 52, 58 n Use bivalent vaccine (Cervarix), 4-valent vaccine (high risk types) in 16-26 year-old females (Gardasil), or 9-valent vaccine (Gardasil 9)

n ~ 97% reduction in cervical, vaginal, vulvar Males: vaccinate routinely through age 21 pre-cancers due to types 31, 33, 45, 52, 58 n Extend to age 26 for MSM or immunocompromise compared with Gardasil n Use 4-valent vaccine (Gardasil) or 9-valent vaccine (Gardasil 9) 5 additional types account for about 20% of cervical cancers 3-dose series for all vaccines

n Okay to continue series with a different vaccine MMWR 2015;65(11):300-304

HPV Vaccines HPV Vaccine: External Genital Lesions

Excellent efficacy in studies (nearly 100%) in preventing infection with HPV types included in vaccine, if not previously infected Prevent cervical and anal intraepithelial neoplasia

Greatest benefit before onset of sexual activity / • 4065 healthy men and boys ages 16 – 26 infection with HPV • Randomized, double-blind, placebo controlled No protection against types with which already • 36 external genital lesions in vaccine group, 89 in infected at time of vaccination placebo group (intent to treat efficacy 60%) • In seronegative group with all doses received, vaccine Some partial cross protection against non-vaccine was 90% effective against genital lesions due to serotypes HPV types 6, 11, 16, 18 (mostly 6 and 11)

13 HPV Vaccines - questions HPV Vaccines - uptake n Expensive In 2013, 57.3% of girls and 34.6% of boys ages n Can a two-dose series be used? 13 – 17 had received one of more doses of HPV vaccine (37.6% and 13.9% received all 3 doses) n Not clear what long-term effect will be on risk of cancer n Girls: modest improvement; Boys: large increase No recommendation to change cervical MMWR 2014;63:620-4 cancer screening based on vaccination HPV due to vaccine types are status dropping in 14-19 year old girls even with limited uptake J Infect Dis 2013;208:385-93

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